Novel pharmaceutical formulation

ABSTRACT

The present invention is directed to a pharmaceutical composition comprising a pharmaceutically effective amount of guaifenesin, naproxen and at least one further active which is selected to be an antitussive, a decongestant or an antihistamine.

The present invention relates to a novel pharmaceutical formulation.

In particular, the present invention is directed to a sustained releaseformulation for oral administration comprising guaifenesin, naproxen andat least one additional active drug ingredient.

Pharmaceutical compositions comprising combinations of actives arewell-known in the prior art. For example, many OTC cold & flu remediesinclude an anti-inflammatory together with an antitussive or coughsuppressant. In addition, there are a number of pain killers which arebased on a combination of one or more of ibuprofen, aspirin, paracetamoland codeine. There are also available immediate release products whichcombine more than two actives. For example, the Tylenol® range includesproducts which combine paracetamol, dextromethorphan & guaifenesin.However, as these products are immediate release products re-dosing isrequired every 4 to 6 hours in order to maintain a therapeutic effect.

However, there is no specific teaching in the prior art of a sustainedrelease dosage form containing guaifenesin, an analgesic and at leastone other pharmaceutically active agent which is capable of sustaining atherapeutic effect for each of the actives for at least twelve hours.

Such a combination would be advantageous to develop as it would providean individual relief from the symptoms of a cough, cold, or flu for anextended period of up to 12 hours. In particular, it would be desirableto develop a product which contains actives that can provide relief fromthe symptoms of a cough or cold as well as an analgesic. The lowsolubility of analgesics, however, can impact the dissolution of otheractive compounds in a combination product. This is particularly true inconventional extended release products where release control isdependent on the erosion of a polymer matrix.

In the area of solid single-dose combination products, such as tabletsor caplets, most of the prior art is directed towards combinations oftwo different actives, each active being contained in a separate layerfrom the other with the third layer acting as a barrier to prevent anynegative interactions between the active-containing layers.

WO 00/059479 discloses a novel pharmaceutical dosage form that providespulsatile delivery of methylphenidate. WO 99/17745 describes acontrolled-release monolithic system for oral administration comprisinga disintegrating layer, an erodible layer and a swelling layer, of whichtwo are external and one is intermediate, each layer containing one ormore drugs.

According to a first aspect of the present invention there is provided apharmaceutical composition comprising a pharmaceutically effectiveamount of at least three different pharmaceutical actives selected fromexpectorant, an analgesic and at least one further active which isselected to be an antitussive, a decongestant or an antihistaminewherein the composition provides a therapeutic effect in respect of eachactive for a period of up to 12 hours.

Typically the analgesic is selected to be an NSAID. The NSAID can beselected from naproxen, ketoprofen, diclofenac, ibuprofen orflurbiprofen.

The expectorant can be guaifenesin.

The at least one other drug can be selected from an antitussive such asdextromethorphan, codeine, codeine phosphate, codeine sulphate,diphenhydramine citrate, and diphenhydramine hydrochloride, adecongestant such as phenylephrine hydrochloride, phenylpropanolaminehydrochloride, pseudoephedrine or ephedrine, an antihistamine such aschlorpheniramine maleate, brompheniramine maleate, phenindaminetartrate, pyrilamine maleate, doxylamine succinate, phenyltoloxaminecitrate, diphenhydramine hydrochloride, promethazine, and clemastinefumerate, or a combination thereof. Preferred actives aredextromethorphan or pseudoephedrine.

The total amount of expectorant can be from about 200 mg-2400 mg,preferably about 600 mg-1200 mg. A preferred amount of expectorant is600 mg. In an alternative embodiment, a preferred amount is 1200 mg.

The total amount of analgesic can be from about 5-4000 mg, preferably110-220 mg. A preferred amount of analgesic is 110 mg. In an alternativeembodiment, a preferred amount is 220 mg.

When the other drug is selected to be dextromethorphan, the total amountof said dextromethorphan can be from about 10-120 mg, preferably 15-60mg. More preferably, the amount of dextromethorphan is 25-35 mg. Apreferred amount of dextromethorphan is 30 mg. In an alternativeembodiment, a preferred amount is 60 mg.

When the at least one other drug is selected to be pseudoephedrine, thetotal amount of said pseudoephedrine can be from about 10-240 mg,preferably 60-120 mg.

In a preferred combination of pharmaceutically active ingredients theexpectorant is guaifenesin, the analgesic is naproxen and theantitussive is dextromethorphan.

The ratio of guaifenesin:naproxen:dextromethorphan can be from about40:8:1 to about 10:3:1. A preferred ratio from 22:4:1 to 17:3:1. A mostpreferred ratio is 20:3.67:1.

The ratio of guaifensin:naproxen can be from about 1:1 to about 10:1,preferably from about 2:1 to about 7:1, more preferably from about 4:1to about 6:1. A preferred ratio is about 5.45:1.

The ratio of the naproxen:dextromethorphan can be from about 1:1 toabout 10:1, preferably from about 2:1 to about 7:1, more preferably fromabout 3:1 to about 5:1. A preferred ratio is about 3.67:1.

When an active other than dextromethorphan is used the ratio ofnaproxen:antitussive/decongestant/antihistamine can be from 10:1 to 2:1.

When flurbiprofen is selected to be the analgesic, the ratio ofexpectorant:analgesic:antitussive/decongestant/antihistamine can be from25:5:1 to 5:0.5:1. The ratio of expectorant:analgesic can be from 10:1to 5:1. The ratio of analgesic:antitussive/decongestant/antihistaminecan be from 1:1.5-1:0.2.

When ibuprofen is selected to be the analgesic, the ratio ofexpectorant:analgesic:antitussive/decongestant/antihistamine can be from25:30:1 to 5:5:1. The ratio of expectorant:analgesic can be from 1:1 to1:5. The ratio of analgesic:antitussive/decongestant/antihistamine canbe from 30:1-5:1.

When diclofenac is selected to be the analgesic, the ratio ofexpectorant:analgesic:antitussive/decongestant/antihistamine can be from25:5:1 to 5:0.5:1. The ratio of expectorant:analgesic can be from 20:1to 5:1. The ratio of analgesic:antitussive/decongestant/antihistaminecan be from 1:2-1:0.2.

When ketoprofen is selected to be the analgesic, the ratio ofexpectorant:analgesic:antitussive/decongestant/antihistamine can be from25:5:1 to 5:0.5:1. The ratio of expectorant:analgesic can be from 10:1to 5:1. The ratio of analgesic:antitussive/decongestant/antihistaminecan be from 1:1.5-1:0.2.

The composition can be in the form of one or more tablets, caplets, orcapsules, gel, elixir, suspension, syrup, emulsion, powder, or granules.Typically, the composition is in the form of either a soft capsule or ahard gel capsule. When the composition is in the form of more than onetablets or caplets, the more than one tablets or caplets are containedwithin a single capsule. The capsule can be made of any suitablematerial, but is typically made of a gelatin material, hydroxyl propylmethyl cellulose or an alginate. The capsule can be in the form ofeither a soft capsule or a hard gel capsule.

The composition can comprise immediate and sustained release portions.As set forth herein, “portion” means a part of a whole, either separatedor integrated with it. Thus, a product with two or more portions mayhave, but does not necessarily require, separate or discrete structuralelements. As further set forth herein “sustained release” refers to atype of “modified release”, and these terms are used interchangeablythroughout.

The analgesic can be incorporated into the composition such that it isthe sole active in the portion in which it is contained.

Typically, the composition is provided with both sustained-release andimmediate-release portions comprising the expectorant.

In a preferred embodiment the composition comprises a first immediaterelease portion which comprises guaifenesin and a decongestant or anantitussive, a second immediate release portion which comprisesnaproxen, and a sustained release portion which comprises guaifenesinand a decongestant or an antitussive. In further preferred embodimentsthe antitussive can be selected to be dextromethorphan or thedecongestant can be selected to be pseudoephedrine.

According to a second aspect of the present invention there is provideda pharmaceutical composition comprising a pharmaceutically effectiveamount of guaifenesin, naproxen and at least one further active which isselected to be an antitussive, a decongestant or an antihistamine.

The at least one other drug can be selected from an antitussive such asdextromethorphan, codeine, codeine phosphate, codeine sulphate,diphenhydramine citrate, and diphenhydramine hydrochloride, adecongestant such as phenylephrine hydrochloride, phenylpropanolaminehydrochloride, pseudoephedrine or ephedrine, an antihistamine such aschlorpheniramine maleate, brompheniramine maleate, phenindaminetartrate, pyrilamine maleate, doxylamine succinate, phenyltoloxaminecitrate, diphenhydramine hydrochloride, promethazine, and clemastinefumerate, or a combination thereof. Preferred actives aredextromethorphan or pseudoephedrine.

The total amount of guaifenesin can be from about 200 mg-2400 mg,preferably about 600 mg-1200 mg. A preferred amount of expectorant is600 mg. In an alternative embodiment, a preferred amount is 1200 mg.

The total amount of naproxen can be from about 5-400 mg, preferably110-220 mg. A preferred amount of analgesic is 110 mg. In an alternativeembodiment, a preferred amount is 220 mg.

When the other drug is selected to be dextromethorphan, the total amountof said dextromethorphan can be from about 10-120 mg, preferably 15-60mg. More preferably, the amount of dextromethorphan is 25-35 mg. Apreferred amount of dextromethorphan is 30 mg. In an alternativeembodiment, a preferred amount is 60 mg.

When the at least one other drug is selected to be pseudoephedrine, thetotal amount of said pseudoephedrine can be from about 10-240 mg,preferably 60-120 mg.

In a preferred combination of pharmaceutically active ingredients theexpectorant is guaifenesin, the analgesic is naproxen and theantitussive is dextromethorphan.

The ratio of guaifenesin:naproxen:dextromethorphan can be from about40:8:1 to about 10:3:1. A preferred ratio from 22:4:1 to 17:3:1. A mostpreferred ratio is 20:3.67:1.

The ratio of guaifensin:naproxen can be from about 1:1 to about 10:1,preferably from about 2:1 to about 7:1, more preferably from about 4:1to about 6:1. A preferred ratio is about 5.45:1.

The ratio of the naproxen:dextromethorphan can be from about 1:1 toabout 10:1, preferably from about 2:1 to about 7:1, more preferably fromabout 3:1 to about 5:1. A preferred ratio is about 3.67:1.

When an active other than dextromethorphan is used the ratio ofnaproxen:antitussive/decongestant/antihistamine can be from 10:1 to 2:1.

The composition can be in the form of one or more tablets, caplets, orcapsules, gel, elixir, suspension, syrup, emulsion, powder, or granules.Typically, the composition is in the form of a capsule. When thecomposition is in the form of more than one tablets or caplets, the morethan one tablets or caplets are contained within a single capsule. Thecapsule can be made of any suitable material, but is typically made of agelatin material.

The composition can comprise immediate and sustained release portions.

Typically, the composition is provided with both sustained-release andimmediate-release portions comprising the expectorant.

The naproxen can be incorporated into the composition such that it isthe sole active in the portion in which it is contained.

Typically, the composition is provided with both sustained-release andimmediate-release portions comprising guaifenesin.

In a preferred embodiment the composition comprises a first immediaterelease portion which comprises guaifenesin and a decongestant or anantitussive, a second immediate release portion which comprisesnaproxen, and a sustained release portion which comprises guaifenesin.In further preferred embodiments the antitussive can be selected to bedextromethorphan or the decongestant can be selected to bepseudoephedrine.

The composition can be in the form of a tablet, caplet, capsule, gel,elixir, suspension, syrup or emulsion. Typically, the composition is inthe form of a capsule.

In a particularly preferred embodiment of the composition of the firstand second embodiments, the composition comprises guaifenesin, naproxenand dextromethorphan.

The composition according to either of the first or second aspect cancomprise:

-   -   (a) 50-85% Guaifenesin;    -   (b) up to 5% Dextromethorphan or a pharmaceutically acceptable        salt thereof; and    -   (c) 5-30% Naproxen or a pharmaceutically acceptable salt        thereof;

The composition according to either of the first or second aspect cancomprise:

-   -   (a) 55-65% Guaifenesin;    -   (b) 1-5% Dextromethorphan or a pharmaceutically acceptable salt        thereof;    -   (c) 5-15% Naproxen or a pharmaceutically acceptable salt        thereof;    -   (d) 1-10% Controlled release polymers;    -   (e) 0.1-10% Binders;    -   (f) 0.1-5% Disintegrants;    -   (g) 5-25% Diluents; and    -   (h) up to 1% Lubricants.

A preferred embodiment of the composition according to either of thefirst or second aspect can comprise:

-   -   (a) 55-65% Guaifenesin;    -   (b) 1-5% Dextromethorphan or a pharmaceutically acceptable salt        thereof;    -   (c) 5-15% Naproxen or a pharmaceutically acceptable salt        thereof;    -   (d) 1-8% Hypromellose;    -   (e) 10-25% Microcrystalline cellulose;    -   (f) 0.1to 2.5% Povidone;    -   (g) 0.1to 4.0% Croscarmellose Sodium;    -   (h) 0.1to 2.0% Hydroxy Ethyl Cellulose; and    -   (i) up to 1% Magnesium stearate.

An alternative preferred embodiment can comprise:

-   -   (a) 58-63% Guaifenesin;    -   (b) 2-3.5% Dextromethorphan or a pharmaceutically acceptable        salt thereof;    -   (c) 10-12% Naproxen or a pharmaceutically acceptable salt        thereof;    -   (d) 1-2% Hypromellose;    -   (e) 15-25% Microcrystalline cellulose;    -   (f) 1-2% Povidone;    -   (g) 0.5-2.5% Croscarmellose sodium;    -   (h) 0.5 to 1% Hydroxyethyl cellulose; and    -   (i) up to 0.5% Magnesium stearate.

In an alternative embodiment the composition can comprise:

-   -   (a) 55-65% Guaifenesin;    -   (b) 1-5% Dextromethorphan or a pharmaceutically acceptable salt        thereof;    -   (c) 5-15% Naproxen or a pharmaceutically acceptable salt        thereof;    -   (d) 1-8% Hypromellose;    -   (e) 10-25% Microcrystalline cellulose;    -   (f) 0.1 to 2.5% Povidone;    -   (g) 0.1to 2.0% Carbomer;    -   (h) 0.1 2.0% Sodium Starch Glycolate;    -   (i) up to 1% Magnesium stearate; and

An alternative preferred embodiment can comprise:

-   -   (a) 59-65% Guaifenesin;    -   (b) 3-5% Dextromethorphan or a pharmaceutically acceptable salt        thereof;    -   (c) 10-12% Naproxen or a pharmaceutically acceptable salt        thereof;    -   (d) 1-6% Hypromellose;    -   (e) 10-20% Microcrystalline cellulose;    -   (f) 0.3 to 1% Povidone;    -   (g) 0.5-1% Carbomer;    -   (h) 0.1 to 0.5% Sodium Starch Glycolate; and    -   (i) up to 1% Magnesium stearate.

An alternative preferred embodiment can comprise:

-   -   (a) 59-65% Guaifenesin;    -   (b) 3-5% Dextromethorphan or a pharmaceutically acceptable salt        thereof;    -   (c) 10-12% Naproxen or a pharmaceutically acceptable salt        thereof;    -   (d) 1-6% Hypromellose;    -   (e) 10-20% Microcrystalline cellulose;    -   (f) 0.3 to 1% Povidone;    -   (g) 0.5-1% Carbomer;    -   (h) 1-2% Croscarmellose sodium;    -   (i) 0.1 to 0.5% Sodium Starch Glycolate; and    -   (j) up to 1% Magnesium stearate.

An alternative preferred embodiment of the composition according toeither of the first or second aspect can comprise:

-   -   (a) 64-69% Guaifenesin;    -   (b) 3-5% Dextromethorphan or a pharmaceutically acceptable salt        thereof;    -   (c) 12-15% Naproxen or a pharmaceutically acceptable salt        thereof;    -   (d) 3-5% Hypromellose;    -   (e) 9-15% Microcrystalline cellulose;    -   (f) 0.4-0.65% Povidone;    -   (g) 0.75-1.3% Carbomer;    -   (h) 0.5-1% Magnesium stearate; and    -   (i) 0.25-0.5% Sodium starch glycolate.

The composition can further comprise one or more of:

-   -   (j) 0.5-1.5% Lactose;    -   (k) 2.5-3.5% Sodium lauryl sulphate; and    -   (l) 0.1-1.5% Croscarmellose sodium.

An alternative preferred embodiment of the composition according toeither of the first or second aspect can comprise:

-   -   (a) 64-69% Guaifenesin;    -   (b) 3-5% Dextromethorphan or a pharmaceutically acceptable salt        thereof;    -   (c) 12-15% Naproxen or a pharmaceutically acceptable salt        thereof;    -   (d) 0.1-0.6% Hypromellose;    -   (e) 9-15% Microcrystalline cellulose;    -   (f) 0.4-0.65% Povidone;    -   (g) 0.75-1.3% Carbomer;    -   (h) 0.5-1% Magnesium stearate; and    -   (i) 0.25-0.5% Sodium starch glycolate.

The composition can further comprise one or more of:

-   -   (j) 0.5-1.5% Lactose;    -   (k) 2.5-3.5% Sodium lauryl sulphate; and    -   (l) 0.1-1.5% Croscarmellose sodium.

An alternative preferred embodiment of the composition according toeither of the first or second aspect can comprise:

-   -   (a) 63-66% Guaifenesin;    -   (b) 3-5% Dextromethorphan or a pharmaceutically acceptable salt        thereof;    -   (c) 10-12% Naproxen or a pharmaceutically acceptable salt        thereof;    -   (d) 1.75-3.0% Hypromellose;    -   (e) 11-13% Microcrystalline cellulose;    -   (f) 1-2% Povidone;    -   (g) 0.5-0.75% Croscarmellose Sodium;    -   (h) 1-2% Carbomer;    -   (i) 0.1-0.5% Magnesium stearate;    -   (j) 0.5-1.5% Lactose; and optionally    -   (k) 2-3% Sodium Lauryl Sulphate.

An alternative preferred embodiment of the composition according toeither of the first or second aspect can comprise:

-   -   (a) 64-66% Guaifenesin;    -   (b) 3-5% Dextromethorphan or a pharmaceutically acceptable salt        thereof;    -   (c) 11-13% Naproxen or a pharmaceutically acceptable salt        thereof;    -   (d) 1.75-3.0% Hypromellose;    -   (e) 6-8.5% Microcrystalline cellulose;    -   (f) 1-2% Povidone;    -   (g) 1-5% Croscarmellose Sodium;    -   (h) 0.5-1% Carbomer;    -   (i) 0.5-1% Magnesium stearate; and    -   (j) 0.5-1% Crospovidone.

The composition can further include one or more of:

-   -   (k) 2-3% Sodium Lauryl Sulphate; and    -   (l) 6-7% Sodium Bicarbonate.

An alternative preferred embodiment of the composition according toeither of the first or second aspect can comprise:

-   -   (a) 64-66% Guaifenesin;    -   (b) 3-5% Dextromethorphan or a pharmaceutically acceptable salt        thereof;    -   (c) 11-13% Naproxen or a pharmaceutically acceptable salt        thereof;    -   (d) 1.75-3.0% Hypromellose;    -   (e) 6-8.5% Microcrystalline cellulose;    -   (f) 1-2% Povidone;    -   (g) 1-5% Croscarmellose Sodium;    -   (h) 0.5-1% Carbomer; and    -   (i) 0.5-1% Magnesium stearate.

An alternative preferred embodiment of the composition according toeither of the first or second aspect can comprise:

-   -   (a) 62-65% Guaifenesin;    -   (b) 3-5% Dextromethorphan or a pharmaceutically acceptable salt        thereof;    -   (c) 11-13% Naproxen or a pharmaceutically acceptable salt        thereof;    -   (d) 1.75-3.0% Hypromellose;    -   (e) 6-8.5% Microcrystalline cellulose;    -   (f) 1-2% Povidone;    -   (g) 1-5% Croscarmellose Sodium;    -   (h) 0.5-1% Carbomer; and    -   (i) 0.5-1% Magnesium stearate;    -   (j) 2-3% Sodium Lauryl Sulphate; and    -   (k) 5-8% Sodium Bicarbonate.

An alternative preferred embodiment of the composition according toeither of the first or second aspect can comprise:

-   -   (a) 58-60% Guaifenesin;    -   (b) 2-3% Dextromethorphan or a pharmaceutically acceptable salt        thereof;    -   (c) 10-11% Naproxen or a pharmaceutically acceptable salt        thereof;    -   (d) 2-3% Hypromellose;    -   (e) 7-8% Microcrystalline cellulose;    -   (f) 1-2% Povidone;    -   (g) 2-3% Croscarmellose Sodium;    -   (h) 0.1-0.2% Magnesium stearate;    -   (i) 0.5-1% Crospovidone;    -   (j) 1-3% Hydroxyethyl cellulose;    -   (k) 2-3% Sodium Lauryl Sulphate; and    -   (l) 9-10% Sodium bicarbonate.

An alternative preferred embodiment of the composition according toeither of the first or second aspect can comprise:

-   -   (a) 64-66% Guaifenesin;    -   (b) 3-5% Dextromethorphan or a pharmaceutically acceptable salt        thereof;    -   (c) 11-13% Naproxen or a pharmaceutically acceptable salt        thereof;    -   (d) 2-3% Hypromellose;    -   (e) 6-7% Microcrystalline cellulose;    -   (f) 1-2% Povidone;    -   (g) 0.1-0.5% Magnesium stearate;    -   (h) 7-10% Crospovidone; and    -   (i) 1-3% Hydroxyethyl cellulose.

A preferred embodiment of the composition according to either of thefirst or second aspect consists essentially of:

-   -   (a) 55-65% Guaifenesin;    -   (b) 1-5% Dextromethorphan or a pharmaceutically acceptable salt        thereof;    -   (c) 5-15% Naproxen or a pharmaceutically acceptable salt        thereof;    -   (d) 1-8% Hypromellose;    -   (e) 10-25% Microcrystalline cellulose;    -   (f) 0.1to 2.5% Povidone;    -   (g) 0.1to 4.0% Croscarmellose Sodium;    -   (h) 0.1to 2.0% Hydroxy Ethyl Cellulose; and    -   (i) up to 1% Magnesium stearate.

An alternative preferred embodiment consists essentially of:

-   -   (a) 58-63% Guaifenesin;    -   (b) 2-3.5% Dextromethorphan or a pharmaceutically acceptable        salt thereof;    -   (c) 10-12% Naproxen or a pharmaceutically acceptable salt        thereof;    -   (d) 1-2% Hypromellose;    -   (e) 15-25% Microcrystalline cellulose;    -   (f) 1-2% Povidone;    -   (g) 0.5-2.5% Croscarmellose sodium;    -   (h) 0.5 to 1% Hydroxyethyl cellulose; and    -   (i) up to 0.5% Magnesium stearate.

In an alternative embodiment the composition consists essentially of:

-   -   (a) 55-65% Guaifenesin;    -   (b) 1-5% Dextromethorphan or a pharmaceutically acceptable salt        thereof;    -   (c) 5-15% Naproxen or a pharmaceutically acceptable salt        thereof;    -   (d) 1-8% Hypromellose;    -   (e) 10-25% Microcrystalline cellulose;    -   (f) 0.1 to 2.5% Povidone;    -   (g) 0.1to 2.0% Carbomer;    -   (h) 0.1 2.0% Sodium Starch Glycolate;    -   (i) up to 1% Magnesium stearate; and

An alternative preferred embodiment consists essentially of:

-   -   (a) 59-65% Guaifenesin;    -   (b) 3-5% Dextromethorphan or a pharmaceutically acceptable salt        thereof;    -   (c) 10-12% Naproxen or a pharmaceutically acceptable salt        thereof;    -   (d) 1-6% Hypromellose;    -   (e) 10-20% Microcrystalline cellulose;    -   (f) 0.3 to 1% Povidone;    -   (g) 0.5-1% Carbomer;    -   (h) 0.1 to 0.5% Sodium Starch Glycolate; and    -   (i) up to 1% Magnesium stearate.

An alternative preferred embodiment consists essentially of:

-   -   (a) 59-65% Guaifenesin;    -   (b) 3-5% Dextromethorphan or a pharmaceutically acceptable salt        thereof;    -   (c) 10-12% Naproxen or a pharmaceutically acceptable salt        thereof;    -   (d) 1-6% Hypromellose;    -   (e) 10-20% Microcrystalline cellulose;    -   (f) 0.3 to 1% Povidone;    -   (g) 0.5-1% Carbomer;    -   (h) 1-2% Croscarmellose sodium;    -   (i) 0.1 to 0.5% Sodium Starch Glycolate; and    -   (j) up to 1% Magnesium stearate.

An alternative preferred embodiment of the composition according toeither of the first or second aspect consists essentially of:

-   -   (a) 64-69% Guaifenesin;    -   (b) 3-5% Dextromethorphan or a pharmaceutically acceptable salt        thereof;    -   (c) 12-15% Naproxen or a pharmaceutically acceptable salt        thereof;    -   (d) 3-5% Hypromellose;    -   (e) 9-15% Microcrystalline cellulose;    -   (f) 0.4-0.65% Povidone;    -   (g) 0.75-1.3% Carbomer;    -   (h) 0.5-1% Magnesium stearate; and    -   (i) 0.25-0.5% Sodium starch glycolate.

An alternative preferred embodiment of the composition according toeither of the first or second aspect consists essentially of:

-   -   (a) 64-69% Guaifenesin;    -   (b) 3-5% Dextromethorphan or a pharmaceutically acceptable salt        thereof;    -   (c) 12-15% Naproxen or a pharmaceutically acceptable salt        thereof;    -   (d) 0.1-0.5% Hypromellose;    -   (e) 9-15% Microcrystalline cellulose;    -   (f) 0.4-0.65% Povidone;    -   (g) 0.75-1.3% Carbomer;    -   (h) 0.5-1% Magnesium stearate; and    -   (i) 0.25-0.5% Sodium starch glycolate.

An alternative preferred embodiment of the composition according toeither of the first or second aspect consists essentially of:

-   -   (a) 64-69% Guaifenesin;    -   (b) 3-5% Dextromethorphan or a pharmaceutically acceptable salt        thereof;    -   (c) 12-15% Naproxen or a pharmaceutically acceptable salt        thereof;    -   (d) 3-5% Hypromellose;    -   (e) 9-15% Microcrystalline cellulose;    -   (f) 0.4-0.65% Povidone;    -   (g) 0.75-1.3% Carbomer;    -   (h) 0.5-1% Magnesium stearate;    -   (i) 0.25-0.5% Sodium starch glycolate;    -   (j) 0.5-1.5% Lactose; and    -   (k) 0.1-1.5% Croscarmellose sodium.

An alternative preferred embodiment of the composition according toeither of the first or second aspect consists essentially of:

-   -   (a) 64-69% Guaifenesin;    -   (b) 3-5% Dextromethorphan or a pharmaceutically acceptable salt        thereof;    -   (c) 12-15% Naproxen or a pharmaceutically acceptable salt        thereof;    -   (d) 0.1-0.6% Hypromellose;    -   (e) 9-15% Microcrystalline cellulose;    -   (f) 0.4-0.65% Povidone;    -   (g) 0.75-1.3% Carbomer;    -   (h) 0.5-1% Magnesium stearate;    -   (i) 0.25-0.5% Sodium starch glycolate;    -   (j) 0.5-1.5% Lactose; and    -   (k) 0.1-1.5% Croscarmellose sodium.

An alternative preferred embodiment of the composition according toeither of the first or second aspect consists essentially of:

-   -   (a) 63-66% Guaifenesin;    -   (b) 3-5% Dextromethorphan or a pharmaceutically acceptable salt        thereof;    -   (c) 10-12% Naproxen or a pharmaceutically acceptable salt        thereof;    -   (d) 1.75-3.0% Hypromellose;    -   (e) 11-13% Microcrystalline cellulose;    -   (f) 1-2% Povidone;    -   (g) 0.5-0.75% Croscarmellose Sodium;    -   (h) 1-2% Carbomer;    -   (i) 0.1-0.5% Magnesium stearate; and    -   (j) 0.5-1.5% Lactose.

An alternative preferred embodiment of the composition according toeither of the first or second aspect consists essentially of:

-   -   (a) 64-69% Guaifenesin;    -   (b) 3-5% Dextromethorphan or a pharmaceutically acceptable salt        thereof;    -   (c) 12-15% Naproxen or a pharmaceutically acceptable salt        thereof;    -   (d) 3-5% Hypromellose;    -   (e) 9-15% Microcrystalline cellulose;    -   (f) 0.4-0.65% Povidone;    -   (g) 0.75-1.3% Carbomer;    -   (h) 0.5-1% Magnesium stearate;    -   (i) 0.25-0.5% Sodium starch glycolate;    -   (j) 2-3.5% Sodium Lauryl Sulphate; and    -   (k) 0.1-1.5% Croscarmellose sodium.

An alternative preferred embodiment of the composition according toeither of the first or second aspect consists essentially of:

-   -   (a) 64-69% Guaifenesin;    -   (b) 3-5% Dextromethorphan or a pharmaceutically acceptable salt        thereof;    -   (c) 12-15% Naproxen or a pharmaceutically acceptable salt        thereof;    -   (d) 0.1-0.6% Hypromellose;    -   (e) 9-15% Microcrystalline cellulose;    -   (f) 0.4-0.65% Povidone;    -   (g) 0.75-1.3% Carbomer;    -   (h) 0.5-1% Magnesium stearate;    -   (i) 0.25-0.5% Sodium starch glycolate;    -   (j) 2-3.5% Sodium Lauryl Sulphate; and    -   (k) 0.1-1.5% Croscarmellose sodium.

An alternative preferred embodiment of the composition according toeither of the first or second aspect consists essentially of:

-   -   (a) 64-69% Guaifenesin;    -   (b) 3-5% Dextromethorphan or a pharmaceutically acceptable salt        thereof;    -   (c) 12-15% Naproxen or a pharmaceutically acceptable salt        thereof;    -   (d) 0.1-0.6% Hypromellose;    -   (e) 9-15% Microcrystalline cellulose;    -   (f) 0.4-0.65% Povidone;    -   (g) 0.75-1.3% Carbomer;    -   (h) 0.5-1% Magnesium stearate;    -   (i) 0.25-0.5% Sodium starch glycolate;    -   (j) 2-3.5% Sodium Lauryl Sulphate; and    -   (k) 0.1-1.5% Croscarmellose sodium.

An alternative preferred embodiment of the composition according toeither of the first or second aspect consists essentially of:

-   -   (a) 63-66% Guaifenesin;    -   (b) 3-5% Dextromethorphan or a pharmaceutically acceptable salt        thereof;    -   (c) 10-12% Naproxen or a pharmaceutically acceptable salt        thereof;    -   (d) 1.75-3.0% Hypromellose;    -   (e) 11-13% Microcrystalline cellulose;    -   (f) 1-2% Povidone;    -   (g) 0.5-0.75% Croscarmellose Sodium;    -   (h) 1-2% Carbomer;    -   (i) 0.1-0.5% Magnesium stearate;    -   (j) 0.5-1.5% Lactose; and    -   (k) 2-3% Sodium Lauryl Sulphate.

An alternative preferred embodiment of the composition according toeither of the first or second aspect consists essentially of:

-   -   (a) 64-66% Guaifenesin;    -   (b) 3-5% Dextromethorphan or a pharmaceutically acceptable salt        thereof;    -   (c) 11-13% Naproxen or a pharmaceutically acceptable salt        thereof;    -   (d) 1.75-3.0% Hypromellose;    -   (e) 6-8.5% Microcrystalline cellulose;    -   (f) 1-2% Povidone;    -   (g) 1-5% Croscarmellose Sodium;    -   (h) 0.5-1% Carbomer;    -   (i) 0.5-1% Magnesium stearate;    -   (j) 0.5-1% Crospovidone; and    -   (k) 2-3% Hypromellose.

An alternative preferred embodiment of the composition according toeither of the first or second aspect consists essentially of:

-   -   (a) 64-66% Guaifenesin;    -   (b) 3-5% Dextromethorphan or a pharmaceutically acceptable salt        thereof;    -   (c) 11-13% Naproxen or a pharmaceutically acceptable salt        thereof;    -   (d) 1.75-3.0% Hypromellose;    -   (e) 6-8.5% Microcrystalline cellulose;    -   (f) 1-2% Povidone;    -   (g) 1-5% Croscarmellose Sodium;    -   (h) 0.5-1% Carbomer;    -   (i) 0.5-1% Magnesium stearate;    -   (j) 0.5-1% Crospovidone;    -   (k) 2-3% Hypromellose;    -   (l) 2-3% Sodium Lauryl Sulphate; and    -   (m) 6-7% Sodium Bicarbonate.

An alternative preferred embodiment of the composition according toeither of the first or second aspect consists essentially of:

-   -   (a) 58-60% Guaifenesin;    -   (b) 2-3% Dextromethorphan or a pharmaceutically acceptable salt        thereof;    -   (c) 10-11% Naproxen or a pharmaceutically acceptable salt        thereof;    -   (d) 2-3% Hypromellose;    -   (e) 7-8% Microcrystalline cellulose;    -   (f) 1-2% Povidone;    -   (g) 2-3% Croscarmellose Sodium;    -   (h) 0.1-0.2% Magnesium stearate;    -   (i) 0.5-1% Crospovidone;    -   (j) 1-3% Hydroxyethyl cellulose;    -   (k) 2-3% Sodium Lauryl Sulphate; and    -   (l) 9-10% Sodium bicarbonate.

An alternative preferred embodiment of the composition according toeither of the first or second aspect consists essentially of:

-   -   (a) 64-66% Guaifenesin;    -   (b) 3-5% Dextromethorphan or a pharmaceutically acceptable salt        thereof;    -   (c) 11-13% Naproxen or a pharmaceutically acceptable salt        thereof;    -   (d) 2-3% Hypromellose;    -   (e) 6-7% Microcrystalline cellulose;    -   (f) 1-2% Povidone;    -   (g) 0.1-0.5% Magnesium stearate;    -   (h) 7-10% Crospovidone; and    -   (i) 1-3% Hydroxyethyl cellulose.

An alternative preferred embodiment of the composition according toeither of the first or second aspect consists essentially of:

-   -   (a) 62-65% Guaifenesin;    -   (b) 3-5% Dextromethorphan or a pharmaceutically acceptable salt        thereof;    -   (c) 11-13% Naproxen or a pharmaceutically acceptable salt        thereof;    -   (d) 1.75-3.0% Hypromellose;    -   (e) 6-8.5% Microcrystalline cellulose;    -   (f) 1-2% Povidone;    -   (g) 1-5% Croscarmellose Sodium;    -   (h) 0.5-1% Carbomer; and    -   (i) 0.5-1% Magnesium stearate;    -   (j) 2-3% Sodium Lauryl Sulphate; and    -   (k) 5-8% Sodium Bicarbonate.

An alternative preferred embodiment of the composition according toeither of the first or second aspect consists essentially of:

-   -   (a) 64-66% Guaifenesin;    -   (b) 3-5% Dextromethorphan or a pharmaceutically acceptable salt        thereof;    -   (c) 11-13% Naproxen or a pharmaceutically acceptable salt        thereof;    -   (d) 1.75-3.0% Hypromellose;    -   (e) 6-8.5% Microcrystalline cellulose;    -   (f) 1-2% Povidone;    -   (g) 1-5% Croscarmellose Sodium;    -   (h) 0.5-1% Carbomer; and    -   (i) 0.5-1% Magnesium stearate.

According to a third aspect of the present invention there is provided apharmaceutical dosage form which comprises at least 3 distinct portionswherein 2 of the portions have immediate release characteristics and a3^(rd) has modified release characteristics wherein one of the immediaterelease portions comprises an expectorant and a second active which isan antitussive or a decongestant and the second immediate releaseportion comprises an analgesic having a half-life of twelve hours andwherein the modified release portion comprises guaifenesin and a secondactive which is an antitussive or a decongestant.

The dosage form can comprise a first composition which comprises bothimmediate and modified release portions of the expectorant and thesecond active which is an antitussive or a decongestant and a secondcomposition which comprises an analgesic having a therapeutic effect oftwelve hours.

The analgesic can be incorporated into the composition such that it isthe sole active in the portion in which it is contained.

In preferred embodiments of the compositions of the first, second andthird aspects of the present invention the analgesic-containingimmediate release portion can comprise:

-   -   (a) 50-52% Naproxen or a pharmaceutically acceptable salt        thereof;    -   (b) 35-40% Microcrystalline cellulose;    -   (c) up to 5% Povidone;    -   (d) 5-8% Croscarmellose sodium; and    -   (e) up to 1% Magnesium stearate.

In alternative preferred embodiments of the compositions of the first,second and third aspects of the present invention theanalgesic-containing immediate release portion can comprise:

-   -   (a) 70-75% Naproxen or a pharmaceutically acceptable salt        thereof;    -   (b) 20-25% Microcrystalline cellulose;    -   (c) up to 5% Povidone;    -   (d) up to 1% Magnesium stearate.

In further alternative preferred embodiments of the compositions of thefirst, second and third aspects of the present invention theanalgesic-containing immediate release portion can comprise:

-   -   (a) 70-75% Naproxen or a pharmaceutically acceptable salt        thereof;    -   (b) 5-10% Microcrystalline cellulose;    -   (c) up to 5% Povidone;    -   (d) up to 1% Magnesium stearate;    -   (e) 5-10% Lactose; and    -   (f) up to 5% Croscarmellose sodium.

In further alternative preferred embodiments of the compositions of thefirst, second and third aspects of the present invention theanalgesic-containing immediate release portion can comprise:

-   -   (a) 70-75% Naproxen or a pharmaceutically acceptable salt        thereof;    -   (b) 5-10% Microcrystalline cellulose;    -   (c) up to 5% Povidone;    -   (d) up to 1% Magnesium stearate;    -   (e) 5-10% Lactose; and    -   (f) 5-10% Croscarmellose sodium.

In further alternative preferred embodiments of the compositions of thefirst, second and third aspects of the present invention theanalgesic-containing immediate release portion can comprise:

-   -   (a) 70-75% Naproxen or a pharmaceutically acceptable salt        thereof;    -   (b) 5-10% Microcrystalline cellulose;    -   (c) up to 5% Povidone;    -   (d) up to 1% Magnesium stearate;    -   (e) up to 5% Lactose; and    -   (f) 15-20% Sodium Lauryl Sulphate.

In further alternative preferred embodiments of the compositions of thefirst, second and third aspects of the present invention theanalgesic-containing immediate release portion can comprise:

-   -   (a) 70-75% Naproxen or a pharmaceutically acceptable salt        thereof;    -   (b) 5-10% Microcrystalline cellulose;    -   (c) up to 5% Povidone;    -   (d) up to 1% Magnesium stearate;    -   (e) up to 2% Croscarmellose sodium; and    -   (f) 15-20% Sodium Lauryl Sulphate.

In preferred embodiments of the compositions of the first, second andthird aspects of the present invention the guaifenesin-containingimmediate release portion can comprise:

-   -   (a) 30-40% Guaifenesin;    -   (b) up to 5% Dextromethorphan or a pharmaceutically acceptable        salt thereof;    -   (c) 50-60% Microcrystalline cellulose;    -   (d) up to 7% Povidone;    -   (e) up to 7% Croscarmellose sodium; and    -   (f) up to 1% Magnesium stearate.

In alternative preferred embodiments of the compositions of the first,second and third aspects of the present invention preferred embodimentsof the compositions of the present the guaifenesin-containing immediaterelease portion can comprise:

-   -   (a) 40-50% Guaifenesin;    -   (b) up to 5% Dextromethorphan or a pharmaceutically acceptable        salt thereof;    -   (c) 40-50% Microcrystalline cellulose;    -   (d) up to 5% Hypromellose;    -   (e) up to 5% Sodium starch glycolate; and    -   (f) up to 1% Magnesium stearate.

In alternative preferred embodiments of the compositions of the first,second and third aspects of the present invention preferred embodimentsof the compositions of the present the guaifenesin-containing immediaterelease portion can comprise:

-   -   (a) 50-65% Guaifenesin;    -   (b) up to 5% Dextromethorphan or a pharmaceutically acceptable        salt thereof;    -   (c) 25-40% Microcrystalline cellulose;    -   (d) up to 5% Povidone;    -   (e) up to 5% Croscarmellose sodium; and    -   (f) up to 1% Magnesium stearate.

In preferred embodiments of the compositions of the first, second andthird aspects of the present invention the modified release portion cancomprise:

-   -   (a) 80-90% Guaifenesin;    -   (b) up to 5% Dextromethorphan or a pharmaceutically acceptable        salt thereof;    -   (c) up to 10% Hypromellose;    -   (d) up to 5% Carbomer;    -   (e) up to 1.55% Magnesium stearate.

In alternative preferred embodiments of the compositions of the first,second and third aspects of the present invention preferred embodimentsof the compositions of the present invention the modified releaseportion can comprise:

-   -   (a) 80-90% Guaifenesin;    -   (b) 3-6% Dextromethorphan or a pharmaceutically acceptable salt        thereof;    -   (c) up to 5% Hypromellose;    -   (d) up to 2% Hydroxy ethylcellulose;    -   (e) up to 5% Microcrystalline cellulose;    -   (f) up to 1% Magnesium stearate.

In alternative preferred embodiments of the compositions of the first,second and third aspects of the present invention preferred embodimentsof the compositions of the present invention the modified releaseportion can comprise:

-   -   (a) 80-90% Guaifenesin;    -   (b) 3-6% Dextromethorphan or a pharmaceutically acceptable salt        thereof;    -   (c) up to 5% Hypromellose;    -   (d) up to 5% Hydroxy ethylcellulose;    -   (e) up to 5% Microcrystalline cellulose;    -   (f) up to 1% Magnesium stearate.

In preferred embodiments of the compositions of the first, second andthird aspects of the present invention the modified release portion cancomprise:

-   -   (a) 85-90% Guaifenesin;    -   (b) 4-5% Dextromethorphan or a pharmaceutically acceptable salt        thereof;    -   (c) 3-6% Hypromellose;    -   (d) 1-3% Carbomer;    -   (e) 0.5-1% Magnesium stearate.

In preferred embodiments of the compositions of the first, second andthird aspects of the present invention the modified release portion cancomprise:

-   -   (a) 90-93% Guaifenesin;    -   (b) 4-6% Dextromethorphan or a pharmaceutically acceptable salt        thereof;    -   (c) 1-3% Carbomer;    -   (d) 0.5-1% Magnesium stearate.

In preferred embodiments of the compositions of the first, second andthird aspects of the present invention the analgesic-containingimmediate release portion consists essentially of:

-   -   (a) 50-52% Naproxen or a pharmaceutically acceptable salt        thereof;    -   (b) 35-40% Microcrystalline cellulose;    -   (c) up to 5% Povidone;    -   (d) 5-8% Croscarmellose sodium; and    -   (e) up to 1% Magnesium stearate.

In alternative preferred embodiments of the compositions of the first,second and third aspects of the present invention theanalgesic-containing immediate release portion consists essentially of:

-   -   (a) 70-75% Naproxen or a pharmaceutically acceptable salt        thereof;    -   (b) 20-25% Microcrystalline cellulose;    -   (c) up to 5% Povidone;    -   (d) up to 1% Magnesium stearate.

In further alternative preferred embodiments of the compositions of thefirst, second and third aspects of the present invention theanalgesic-containing immediate release portion consists essentially of:

-   -   (a) 70-75% Naproxen or a pharmaceutically acceptable salt        thereof;    -   (b) 5-10% Microcrystalline cellulose;    -   (c) up to 5% Povidone;    -   (d) up to 1% Magnesium stearate;    -   (e) 5-10% Lactose; and    -   (f) up to 5% Croscarmellose sodium.

In further alternative preferred embodiments of the compositions of thefirst, second and third aspects of the present invention theanalgesic-containing immediate release portion consists essentially of:

-   -   (a) 70-75% Naproxen or a pharmaceutically acceptable salt        thereof;    -   (b) 5-10% Microcrystalline cellulose;    -   (c) up to 5% Povidone;    -   (d) up to 1% Magnesium stearate;    -   (e) 5-10% Lactose; and    -   (f) 5-10% Croscarmellose sodium.

In further alternative preferred embodiments of the compositions of thefirst, second and third aspects of the present invention theanalgesic-containing immediate release portion consists essentially of:

-   -   (a) 70-75% Naproxen or a pharmaceutically acceptable salt        thereof;    -   (b) 5-10% Microcrystalline cellulose;    -   (c) up to 5% Povidone;    -   (d) up to 1% Magnesium stearate;    -   (e) up to 5% Lactose; and    -   (f) 15-20% Sodium Lauryl Sulphate.

In further alternative preferred embodiments of the compositions of thefirst, second and third aspects of the present invention theanalgesic-containing immediate release portion consists essentially of:

-   -   (a) 70-75% Naproxen or a pharmaceutically acceptable salt        thereof;    -   (b) 5-10% Microcrystalline cellulose;    -   (c) up to 5% Povidone;    -   (d) up to 1% Magnesium stearate;    -   (e) up to 2% Croscarmellose sodium; and    -   (f) 15-20% Sodium Lauryl Sulphate.

In preferred embodiments of the compositions of the first, second andthird aspects of the present invention the guaifenesin-containingimmediate release portion consists essentially of:

-   -   (a) 30-40% Guaifenesin;    -   (b) up to 5% Dextromethorphan or a pharmaceutically acceptable        salt thereof;    -   (c) 50-60% Microcrystalline cellulose;    -   (d) up to 7% Povidone;    -   (e) up to 7% Croscarmellose sodium; and    -   (f) up to 1% Magnesium stearate.

In alternative preferred embodiments of the compositions of the first,second and third aspects of the present invention preferred embodimentsof the compositions of the present the guaifenesin-containing immediaterelease portion consists essentially of:

-   -   (a) 40-50% Guaifenesin;    -   (b) up to 5% Dextromethorphan or a pharmaceutically acceptable        salt thereof;    -   (c) 40-50% Microcrystalline cellulose;    -   (d) up to 5% Hypromellose;    -   (e) up to 5% Sodium starch glycolate; and    -   (f) up to 1% Magnesium stearate.

In alternative preferred embodiments of the compositions of the first,second and third aspects of the present invention preferred embodimentsof the compositions of the present the guaifenesin-containing immediaterelease portion consists essentially of:

-   -   (a) 50-65% Guaifenesin;    -   (b) up to 5% Dextromethorphan or a pharmaceutically acceptable        salt thereof;    -   (c) 25-40% Microcrystalline cellulose;    -   (d) up to 5% Povidone;    -   (e) up to 5% Croscarmellose sodium; and    -   (f) up to 1% Magnesium stearate.

In preferred embodiments of the compositions of the first, second andthird aspects of the present invention the modified release portionconsists essentially of:

-   -   (a) 80-90% Guaifenesin;    -   (b) up to 5% Dextromethorphan or a pharmaceutically acceptable        salt thereof;    -   (c) up to 10% Hypromellose;    -   (d) up to 5% Carbomer;    -   (e) up to 1.55% Magnesium stearate.

In alternative preferred embodiments of the compositions of the first,second and third aspects of the present invention preferred embodimentsof the compositions of the present invention the modified immediaterelease portion consists essentially of:

-   -   (a) 80-90% Guaifenesin;    -   (b) 3-6% Dextromethorphan or a pharmaceutically acceptable salt        thereof;    -   (c) up to 5% Hypromellose;    -   (d) up to 2% Hydroxy ethylcellulose;    -   (e) up to 5% Microcrystalline cellulose;    -   (f) up to 1% Magnesium stearate.

In alternative preferred embodiments of the compositions of the first,second and third aspects of the present invention preferred embodimentsof the compositions of the present invention the modified immediaterelease portion consists essentially of:

-   -   (a) 80-90% Guaifenesin;    -   (b) 3-6% Dextromethorphan or a pharmaceutically acceptable salt        thereof;    -   (c) up to 5% Hypromellose;    -   (d) up to 5% Hydroxy ethylcellulose;    -   (e) up to 5% Microcrystalline cellulose;    -   (f) up to 1% Magnesium stearate.

In preferred embodiments of the compositions of the first, second andthird aspects of the present invention the modified release portionconsists essentially of:

-   -   (a) 85-90% Guaifenesin;    -   (b) 4-5% Dextromethorphan or a pharmaceutically acceptable salt        thereof;    -   (c) 3-6% Hypromellose;    -   (d) 1-3% Carbomer;    -   (e) 0.5-1% Magnesium stearate.

In preferred embodiments of the compositions of the first, second andthird aspects of the present invention the modified release portionconsists essentially of:

-   -   (a) 90-93% Guaifenesin;    -   (b) 4-6% Dextromethorphan or a pharmaceutically acceptable salt        thereof;    -   (c) 1-3% Carbomer;    -   (d) 0.5-1% Magnesium stearate.

For the avoidance of doubt the present disclosure covers all possiblecombinations of the preferred embodiments of the immediate releaseanalgesic-containing portion, the immediate releaseguaifenesin-containing portion and the modified release containingportion to give a composition having each of an immediate releaseanalgesic-containing portion, an immediate releaseguaifenesin-containing portion and a modified release containingportion.

Modified release polymers that can be used in the compositions of thepresent invention include Acacia, Adipic Acid, Agar, Alginic Acid,Aliphatic Polyesters, Calcium Alginate, Carbomer, Carrageenan, CastorOil, Cellaburate, Cellulose Acetate, Ceratonia, Colophony, Copovidone,Glyceryl Behenate, Glyceryl Monooleate, Glyceryl Monostearate, GlycerylPalmitostearate, Hydroxypropyl Betadex, Hydroxypropyl Cellulose,Hydroxyethyl Cellulose, Hypromellose, Hypromellose Acetate Succinate,Methylcellulose, Polacrilin Potassium, Polycarbophil, Polydextrose,Polymethacrylates, Polyoxylglycerides, Polyvinyl Acetate Dispersion,Shellac, Sodium Alginate, Sodium Hyaluronate, Modified Starch, SucroseStearate, Microcrystalline Wax, White Wax, Yellow Wax, Xanthan Gum,Zein.

Hydrophilic polymers suitable for use in the sustained release portioninclude: one or more natural or partially or totally synthetichydrophilic gums such as acacia, gum tragacanth, locust bean gum, guargum, or karaya gum, modified cellulosic substances such asmethylcellulose, hydroxymethylcellulose, hydroxypropyl methylcellulose,hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxyethylcellulose,carboxyethylcellulose; proteinaceous substances such as agar, pectin,carrageen, and alginates; and other hydrophilic polymers such ascarboxypolymethylene, gelatin, casein, zein, bentonite, magnesiumaluminium silicate, polysaccharides, modified starch derivatives, andother hydrophilic polymers known to those of skill in the art or acombination of such polymers.

These hydrophilic polymers gel and dissolve slowly in aqueous acidicmedia thereby allowing the guaifenesin to diffuse from the gel in thestomach. When the gel reaches the intestines, it dissolves in controlledquantities in the higher pH medium, where the guaifenesin itself isfairly absorbable, to allow sustained release of guaifenesin throughoutthe digestive tract. Preferred hydrophilic polymers are thehydroxypropyl methylcelluloses such as those manufactured by The DowChemical Company and known as METHOCEL ethers. In one preferredembodiment of a sustained release formulation the hydrophilic polymer isa METHOCEL ether known as METHOCEL E10M.

Water-insoluble polymers which arc suitable for use in the sustainedrelease portion are polymers which generally do not dissolve insolutions of a pH below 5, and dissolve more slowly in basic solutionsthan the hydrophilic polymer. Because the polymer is insoluble in low pHenvironments such as those found in gastric fluid, it aids in retardingdrug release in those regions. Likewise, because the polymer dissolvesmore slowly in solutions of higher pH than hydrophilic polymers, it aidsin retarding drug release throughout the intestines. This overalldelayed release results in a more uniform serum concentration ofguaifenesin.

The water-insoluble polymers suitable for use in the sustained releaseportion include: polyacrylic acids, acrylic resins, acrylic latexdispersions, cellulose acetate phthalate, polyvinyl acetate phthalate,hydroxypropyl methylcellulose phthalate, carbomer and other polymerscommon to those of skill in the art. In a preferred embodiment, asustained release formulation comprises the acrylic resin CARBOPOL 974Psupplied by BF Goodrich.

The sustained release portion of the present invention may furthercomprise pharmaceutical additives including, but not limited to:lubricants such as magnesium stearate, calcium stearate, zinc stearate,powdered stearic acid, hydrogenated vegetable oils, talc, polyethyleneglycol, and mineral oil; colorants such as Emerald Green Lake andvarious FD&C colors; binders such as sucrose, lactose, gelatin, starchpaste, acacia, tragacanth, povidone polyethylene glycol, Pullulan andcorn syrup; glidants such as colloidal silicon dioxide and talc; surfaceactive agents such as sodium lauryl sulfate, dioctyl sodiumsulfosuccinate, tricthanolamine, polyoxyethylene sorbitan, poloxalkol,and quarternary ammonium salts; preservatives and stabilizers;excipients such as lactose, mannitol, glucose, fructose, xylose,galactose, sucrose, maltose, xylitol, sorbitol, chloride, sulfate andphosphate salts of potassium, sodium, and magnesium; and/or any otherpharmaceutical additives known to those of skill in the art.

Colorants include, but are not limited to, Emerald Green Lake, FD&C Red#40, FD&C Yellow #6, FD&C Yellow #10, or FD&C Blue #1. In one preferredembodiment, a sustained release portion further comprises magnesiumstearate and Emerald Green Lake. In another preferred embodiment, asustained release formulation further comprises magnesium stearate andFD&C Blue #1 Aluminium Lake Dye.

The immediate release portion may comprise guaifenesin and variouspharmaceutical additives such as disintegrants, lubricants, colorants,binders, glidants, surface active agents, preservatives, stabilizers, asdescribed above and/or any other pharmaceutical additives known to thoseof skill in the art. Examples of suitable lubricant are as follows:Calcium Stearate, Glyceryl Behenate, Leucine, Magnesium Stearate,Mineral Oil, Myristic Acid, Palm Oil, Palmitic Acid, Poloxamer,Polyethylene Glycol, Potassium Benzoate, Sodium Benzoate, Sodium LaurylSulfate, Sodium Stearate, Sodium Stearyl Fumarate, Stearic Acid, SucroseStearate, Talc, Vegetable Oil, Zinc Stearate. Examples of suitabledisintegrants are as follows: Carboxymethylcellulose Calcium,Carboxymethylcellulose Sodium, Sodium Lauryl Sulphate, SodiumBicarboant, Chitosan, Coilloidal Sillicon Dioxide, CroscarmelloseSodium, Crospovidone, Glycine, Guar Gum, Lactose, Magnesium AluminumSilicate, Polacrilin Potassium, Povidone, Sodium Alginate, Sodium StarchGlycolate. Examples of suitable diluents are as follows: CalciumCarbonate, Calcium Lactate, Calcium Phosphate, Calcium Silicate, CalciumSulfate, Cellaburate, Cellulose Acetate, Microcrystalline Cellulose,Silicified Microcrystalline Cellulose, Corn Syrup Solids, Dextrates,Dextrin, Dextrose, Erythritol, Ethylcellulose, Fructose, Inulin,Isomalt, Kaolin, Lactitol, Lactose, Magnesium Carbonate, MagnesiumOxide, Maltitol, Maltodextrin, Maltose, Mannitol, Triglycerides,Polydextrose, Simethicone, Sodium Bicarbonate, Sodium Carbonate, SodiumChloride, Sorbitol, Sucrose, Sugar, Sulfobutylether β-Cyclodextrin,Sunflower Oil, Talc, Trehalose, Xylitol. Examples of suitable bindersare as follows: Attapulgite, Calcium Carbonate, Calcium Lactate,Ceratonia, Colophony, Copovidone, Ethylcellulose, Ethylene Glycol andVinyl Alcohol Grafted Copolymer, Gelatin, Glucose, HydroxethylmethylCelluose, Magnesium Aluminium Silicate, Methylcellulose, Polycarbophil,Polydextrose, Polyethylene Oxide, Polymethacrylates, Povidone, Pullulan,Vitamin E Polyethylene Glycol Succinate.

For the avoidance of any doubt, reference to a pharmaceutically activecompound includes all enantiomers and stereoisomers thereof, and alsoall pharmaceutically acceptable salts or esters thereof. For example,naproxen includes naproxen sodium, pseudoephedrine includespseudoephedrine hydrochloride, dextromethorphan includesdextromethorphan hydrobromide.

In an alternative embodiment, the immediate release portion whichcomprises guaifenesin may further comprise the additional or moreactives in the form of a drug/active-resin complex.

According to a fourth aspect of the present invention there is provideda sustained-release polymer matrix which consists essentially of acombination of a hydroxy propyl methyl cellulose having a molecularweight of 100,000-500,000 and a hydroxyethyl cellulose having amolecular weight of 500,000-2,000,000.

The molecular weight of hydroxyl propyl methyl cellulose can 200,000 to300,000. A preferred molecular weight is 250,000.

The molecular weight of hydroxyethyl cellulose can 1,000,000 to1,500,000. A preferred molecular weight is 1,300,000.

The ratio of the hydroxyl propyl methyl cellulose:hydroxyethyl celluloseis from 1:1 to 3:1. A preferred ratio is from 2:1 to 2.5:1. A morepreferred ratio is 2.1:1.

According to a fifth aspect of the present invention there is providedthe use of a sustained release polymer matrix as described in the fourthaspect in a pharmaceutical formulation.

The pharmaceutical formulation can comprise at least one active selectedfrom an expectorant, an analgesic, an antihistamine, an antitussive, ora decongestant. The expectorant can be selected to be guaifenesin orn-acetyl cysteine. The analgesic can be selected to be naproxen,ketoprofen, diclofenac, ibuprofen and flurbiprofen. The antitussive canbe selected to be dextromethorphan, codeine, codeine phosphate, codeinesulphate, diphenhydramine citrate, and diphenhydramine hydrochloride.The decongestant can be selected to be phenylephrine hydrochloride,phenylpropanolamine hydrochloride, pseudoephedrine or ephedrine. Theantihistamine can be selected to be chlorpheniramine maleate,brompheniramine maleate, phenindamine tartrate, pyrilamine maleate,doxylamine succinate, phenyltoloxamine citrate, diphenhydraminehydrochloride, promethazine, and clemastine fumerate, or a combinationthereof.

According to a sixth aspect of the present invention there is provided amethod of providing relief from the symptoms of bronchial conditions,coughing and symptoms or diseases associated with coughing comprisingadministering to an individual a composition as described in the first,second or third aspects of the present invention.

According to a seventh aspect of the present invention there is providedthe use of a composition as described in the first, second or thirdaspects of the present invention for the preparation of a medicament forthe treatment of bronchial conditions, coughing and diseases associatedwith coughing.

According to an eighth aspect of the present invention these is providedan immediate release formulation of naproxen having an improveddissolution profile.

In a preferred embodiment the composition can comprise:

-   -   (a) 50-52% Naproxen or a pharmaceutically acceptable salt        thereof;    -   (b) 35-40% Microcrystalline cellulose;    -   (c) up to 5% Povidone;    -   (d) 5-8% Croscarmellose sodium; and    -   (e) up to 1% Magnesium stearate.

In a further preferred embodiment the composition can comprise:

-   -   (a) 70-75% Naproxen or a pharmaceutically acceptable salt        thereof;    -   (b) 20-25% Microcrystalline cellulose;    -   (c) up to 5% Povidone;    -   (d) up to 1% Magnesium stearate.

In a further preferred embodiment the composition can comprise:

-   -   (a) 70-75% Naproxen or a pharmaceutically acceptable salt        thereof;    -   (b) 5-10% Microcrystalline cellulose;    -   (c) up to 5% Povidone;    -   (d) up to 1% Magnesium stearate;    -   (e) 5-10% Lactose; and    -   (f) up to 5% Croscarmellose sodium.

In a further preferred embodiment the composition can comprise:

-   -   (a) 70-75% Naproxen or a pharmaceutically acceptable salt        thereof;    -   (b) 5-10% Microcrystalline cellulose;    -   (c) up to 5% Povidone;    -   (d) up to 1% Magnesium stearate;    -   (e) 5-10% Lactose; and    -   (f) 5-10% Croscarmellose sodium.

In a further preferred embodiment the composition can comprise:

-   -   (a) 70-75% Naproxen or a pharmaceutically acceptable salt        thereof;    -   (b) 5-10% Microcrystalline cellulose;    -   (c) up to 5% Povidone;    -   (d) up to 1% Magnesium stearate;    -   (e) up to 5% Lactose; and    -   (f) 15-20% Sodium Lauryl Sulphate.

In a further preferred embodiment the composition can comprise:

-   -   (a) 70-75% Naproxen or a pharmaceutically acceptable salt        thereof;    -   (b) 5-10% Microcrystalline cellulose;    -   (c) up to 5% Povidone;    -   (d) up to 1% Magnesium stearate;    -   (e) up to 2% Croscarmellose sodium; and    -   (f) 15-20% Sodium Lauryl Sulphate.

In a further preferred embodiment the composition can consistessentially of:

-   -   (a) 50-52% Naproxen or a pharmaceutically acceptable salt        thereof;    -   (b) 35-40% Microcrystalline cellulose;    -   (c) up to 5% Povidone;    -   (d) 5-8% Croscarmellose sodium; and    -   (e) up to 1% Magnesium stearate.

In a further preferred embodiment the composition can consistessentially of:

-   -   (a) 70-75% Naproxen or a pharmaceutically acceptable salt        thereof;    -   (b) 20-25% Microcrystalline cellulose;    -   (c) up to 5% Povidone;    -   (d) up to 1% Magnesium stearate.

In a further preferred embodiment the composition can consistessentially of:

-   -   (a) 70-75% Naproxen or a pharmaceutically acceptable salt        thereof;    -   (b) 5-10% Microcrystalline cellulose;    -   (c) up to 5% Povidone;    -   (d) up to 1% Magnesium stearate;    -   (e) 5-10% Lactose; and    -   (f) up to 5% Croscarmellose sodium.

In a further preferred embodiment the composition can consistessentially of:

-   -   (a) 70-75% Naproxen or a pharmaceutically acceptable salt        thereof;    -   (b) 5-10% Microcrystalline cellulose;    -   (c) up to 5% Povidone;    -   (d) up to 1% Magnesium stearate;    -   (e) 5-10% Lactose; and    -   (f) 5-10% Croscarmellose sodium.

In a further preferred embodiment the composition can consistessentially of:

-   -   (a) 70-75% Naproxen or a pharmaceutically acceptable salt        thereof;    -   (b) 5-10% Microcrystalline cellulose;    -   (c) up to 5% Povidone;    -   (d) up to 1% Magnesium stearate;    -   (e) up to 5% Lactose; and    -   (f) 15-20% Sodium Lauryl Sulphate.

In a further preferred embodiment the composition can consistessentially of:

-   -   (a) 70-75% Naproxen or a pharmaceutically acceptable salt        thereof; (b) 5-10% Microcrystalline cellulose;    -   (c) up to 5% Povidone;    -   (d) up to 1% Magnesium stearate;    -   (e) up to 2% Croscarmellose sodium; and    -   (f) 15-20% Sodium Lauryl Sulphate.

Typically, the composition has a dissolution profile of 68-70% after 10mins and 93-98% after 20 mins when tested using US Pharmacopoeiaapparatus 2 (paddles at 75 rpm at 37° C.) in Fessif media at pH 5.

Typically, the composition has a dissolution profile of 85-90% after 10mins when tested using US Pharmacopoeia apparatus 2 (paddles at 75 rpmat 37° C.) in Fessif media at pH 6.8.

Fessif is a term used in the art to mean Fed State Simulated IntestinalFluid. Fassif is a term used in the art to mean Fasted State SimulatedIntestinal Fluid.

As used herein, the term “about” means that the numerical value isapproximate and small variations would not significantly affect thepractice of the disclosed embodiments. Where a numerical limitation isused, unless indicated otherwise by the context, “about” means thenumerical value can vary by +10% and remain within the scope of thedisclosed embodiments.

As used herein, the term “consisting essentially of” means thecomposition contains the indicated components and may contain additionalcomponents provided that the additional components that are non-activeand do not materially affect the composition's basic characteristics. Asused herein, the term “consisting of” means the composition contains theonly indicated components and excludes other components.

As used herein, the term “up to” means a value greater than zero. Forexample, the term “up to 1%” means that component is present in thecomposition and can be present to an amount of 1%. The term “up to 5%”means that the component is present in the composition and can bepresent to an amount of 5%.

For the avoidance of doubt when the composition of the present inventionis in the form of a tablet or tablets, the values given for both theranges and amounts of the components in the compositions of the presentinvention refer to uncoated tablets. Additional coatings can be added asrequired.

Embodiments of the present invention will now be described by way ofexample only.

EXAMPLE 1

Tablet 1: Naproxen Ingredient mg/tablet % Weight Naproxen Sodium 110.0mg 73.33% Microcrystalline Cellulose 34.45 mg 22.96% Povidone 4.50 mg 3.0% Mg Stearate 1.05 mg  0.7% Total Tablet 150.0 mg 100.0%

Tablet 2: Immediate/Sustained Release Dextromethorphan and GuaifenesinIngredient mg/tablet % Weight Guaifenesin 600.0 mg 76.41% Hypromellose50.00 mg  6.37% MCC 87.52 mg 11.15% Dextromethorphan HBr 30.0 mg  3.82%Carbomer 7.50 mg  0.96% Sodium Starch Glycolate 3.98 mg  0.51% Colourant0.20 mg 0.025% Mg Stearate 6.0 mg  0.76% Total Tablet 785.2 mg 100.0%

EXAMPLE 2

Tablet 1: Naproxen Ingredient mg/tablet % Weight Naproxen Sodium 110.0mg 51.16% Microcrystalline Cellulose 81.00 mg 37.67% Crospovidone 7.50mg  3.49% Croscarmellose sodium 15.00 mg  6.98% Mg Stearate 1.50 mg 0.7% Total Tablet 215.0 mg 100.0%

Tablet 2: Immediate/Sustained Release Dextromethorphan and GuaifenesinIngredient mg/tablet % Weight Guaifenesin 600.0 mg 74.77% Hypromellose19.00 mg  2.37% MCC 129.40 mg 16.12% Dextromethorphan HBr 30.0 mg  3.74%Povidone 7.00 mg  0.87% Croscarmellose Sodium 6.00 mg  0.74% Hydroxyethyl cellulose 9.00 mg  1.12% Colourant 0.20 mg 0.025% Mg Stearate 1.9mg  0.24% Total Layer 802.5 mg 100.0%

EXAMPLE 3

Tablet 1: Naproxen Ingredient mg/tablet % Weight Naproxen Sodium 110.0mg 73.33% Microcrystalline Cellulose 14.55 mg  9.7% Lactose 12.65 mg 8.4% Povidone 4.65 mg  3.1% Croscarmellose sodium 7.15 mg  4.8% MgStearate 1 mg  0.7% Total Tablet 150.0 mg 100.0%

Tablet 2: Immediate/Modified Release Dextromethorphan and GuaifenesinImmediate Release Layer Ingredient mg/tablet % Weight Guaifenesin 200 mg 63.77% Dextromethorphan HBr 10 mg  3.19% Microcrystalline Cellulose 85mg  27.10% Povidone 10 mg  3.19% Croscarmellose Sodium 8.5 mg  2.71% MgStearate 0.15 mg  0.05% Total Layer 313.65 mg 100.00%

Modified Release Layer Ingredient mg/tablet % Weight Guaifenesin 400 mg 84.54% Dextromethorphan HBr 20 mg  4.23% Hypromellose (K100M) 24.5 mg 5.18% Hydroxyethylcellulose 12.25 mg  2.59% Microcrystalline Cellulose14.75 mg  3.12% Colourant 0.1 mg  0.02% Mg Stearate 1.55 mg  0.33% TotalLayer 473.15 mg 100.00% Total Tablet 786.8 mg  100.0%

EXAMPLE 4

Tablet 1: Naproxen Ingredient mg/tablet % Weight Naproxen Sodium 110 mg73.33% Microcrystalline Cellulose 6 mg  4.00% Lactose 5 mg  3.33%Povidone 3 mg  2.00% Sodium lauryl sulfate 25 mg 16.67% Mg Stearate 1 mg 0.67% Total Tablet 150.0 mg 100.0%

Tablet 2: Immediate/Modified Release Dextromethorphan and GuaifenesinImmediate Release Layer Ingredient mg/tablet % Weight Guaifenesin 200 mg 63.77% Dextromethorphan HBr 10 mg  3.19% Microcrystalline Cellulose 85mg  27.10% Povidone 10 mg  3.19% Croscarmellose Sodium 8.5 mg  2.71% MgStearate 0.15 mg  0.05% Total Layer 313.65 mg 100.00%

Modified Release Layer Ingredient mg/tablet % Weight Guaifenesin 400 mg84.54% Dextromethorphan HBr 20 mg  4.23% Hypromellose (K100M) 24.5 mg 5.18% Hydroxyethylcellulose 12.25 mg  2.59% Microcrystalline Cellulose14.75 mg  3.12% Colourant 0.1 mg  0.02% Mg Stearate 1.55 mg  0.33% TotalLayer 473.15 mg 100.00%  Total Tablet 786.8 mg 100.0%

EXAMPLE 5

Tablet 1: Naproxen Ingredient mg/tablet % Weight Naproxen Sodium 110.0mg 73.33%  Microcrystalline Cellulose 14.55 mg 9.7% Lactose 12.65 mg8.4% Povidone 4.65 mg 3.1% Croscarmellose sodium 7.15 mg 4.8% MgStearate 1 mg 0.7% Total Tablet 150.0 mg 100.0% 

Tablet 2: Immediate/Modified Release Dextromethorphan and GuaifenesinImmediate Release Layer Ingredient mg/tablet % Weight Guaifenesin 130 mg54.83% Dextromethorphan HBr 7.00 mg  2.95% Microcrystalline Cellulose85.00 mg 35.85% Povidone 8.00 mg  3.37% Croscarmellose Sodium 7.00 mg 2.95% Mg Stearate 0.10 mg  0.04% Total Layer 237.10 mg 100.00% 

Modified Release Layer Ingredient mg/tablet % Weight Guaifenesin 470 mg86.35%  Dextromethorphan HBr 23 mg 4.23% Hypromellose (K100M) 17 mg3.12% Hydroxyethylcellulose 17 mg 3.12% Microcrystalline Cellulose 15.5mg 2.85% Colourant 0.1 mg 0.02% Mg Stearate 1.7 mg 0.31% Total Layer544.3 mg 100.00%  Total Tablet 781.40 mg 100.0% 

EXAMPLE 6

Tablet 1: Naproxen Ingredient mg/tablet % Weight Naproxen Sodium 110 mg73.33% Microcrystalline Cellulose 6 mg  4.00% Lactose 5 mg  3.33%Povidone 3 mg  2.00% Sodium lauryl sulfate 25 mg 16.67% Mg Stearate 1 mg 0.67% Total Tablet 150.0 mg 100.0%

Tablet 2: Immediate/Modified Release Dextromethorphan and GuaifenesinImmediate Release Layer Ingredient mg/tablet % Weight Guaifenesin 130 mg54.83% Dextromethorphan HBr 7.00 mg  2.95% Microcrystalline Cellulose85.00 mg 35.85% Povidone 8.00 mg  3.37% Croscarmellose Sodium 7.0 mg 2.95% Mg Stearate 0.10 mg  0.04% Total Layer 237.10 mg 100.00% 

Modified Release Layer Ingredient mg/tablet % Weight Guaifenesin 470 mg86.35%  Dextromethorphan HBr 23 mg 4.23% Hypromellose (K100M) 17 mg3.12% Hydroxyethylcellulose 17 mg 3.12% Microcrystalline Cellulose 15.5mg 2.85% Colourant 0.1 mg 0.02% Mg Stearate 1.7 mg 0.31% Total Layer544.3 mg 100.00%  Total Tablet 781.40 mg 100.0% 

EXAMPLE 7

Tablet 1: Naproxen Ingredient mg/tablet % Weight Naproxen Sodium 110 mg73.33% Microcrystalline Cellulose 34.45 mg 22.97% Povidone 4.5 mg  3.00%Mg Stearate 1.05 mg  0.7% Total Tablet 150.0 mg 100.0%

Tablet 2: Immediate/Modified Release Dextromethorphan and GuaifenesinImmediate Release Layer Ingredient mg/tablet % Weight Guaifenesin 85.5mg 47.50% Dextromethorphan HBr 6.75 mg 3.75% Microcrystalline Cellulose78.77 mg 43.76% Hypromellose 4.50 mg 2.50% Sodium Starch Glycolate 3.58mg 1.99% Mg Stearate 0.90 mg 0.50% Total Layer 180.00 mg 100.00%

Modified Release Layer Ingredient mg/tablet % Weight Guaifenesin 514.50mg 88.83%  Dextromethorphan HBr 23.25 mg 4.03% Hypromellose 27.50 mg4.75% Carbomer 8.25 mg 1.42% Colourant 0.22 mg 0.04% Mg Stearate 5.50 mg0.95% Total Layer 579.22 mg 100.00%  Total Tablet 759.22 mg 100.0% 

EXAMPLE 8

Tablet 1: Naproxen Ingredient mg/tablet % Weight Naproxen Sodium 110 mg73.33% Microcrystalline Cellulose 34.45 mg 22.97% Povidone 4.5 mg  3.00%Mg Stearate 1.05 mg  0.7% Total Tablet 150.0 mg 100.0%

Tablet 2: Immediate/Modified Release Dextromethorphan and GuaifenesinImmediate Release Layer Ingredient mg/tablet % Weight Guaifenesin 76.00mg 47.50% Dextromethorphan HBr 6.00 mg 3.75% Microcrystalline Cellulose70.02 mg 43.76% Hypromellose 4.00 mg 2.50% Sodium Starch Glycolate 3.18mg 1.99% Mg Stearate 0.80 mg 0.50% Total Layer 160.00 mg 100.00%

Modified Release Layer Ingredient mg/tablet % Weight Guaifenesin 424.00mg 91.74%  Dextromethorphan HBr 24.00 mg 5.19% Carbomer 9.90 mg 2.14%Colourant 0.26 mg 0.06% Mg Stearate 4.00 mg 0.87% Total Layer 462.16 mg100.00%  Total Tablet 622.16 mg 100.0% 

EXAMPLE 9

Tablet 1: Naproxen Ingredient mg/tablet % Weight Naproxen Sodium 110 mg73.33%  Microcrystalline Cellulose 14.5 mg 9.67% Povidone 4.75 mg 3.17%Mg Stearate 0.75 mg  0.7% Lactose 10.00 mg 6.67% Croscarmellose Sodium10.00 mg 6.67% Total Tablet 150.0 mg 100.0% 

Tablet 2: Immediate/Modified Release Dextromethorphan and GuaifenesinImmediate Release Layer Ingredient mg/tablet % Weight Guaifenesin 85.5mg 47.50% Dextromethorphan HBr 6.75 mg 3.75% Microcrystalline Cellulose78.77 mg 43.76% Hypromellose 4.50 mg 2.50% Sodium Starch Glycolate 3.58mg 1.99% Mg Stearate 0.90 mg 0.50% Total Layer 180.00 mg 100.00%

Modified Release Layer Ingredient mg/tablet % Weight Guaifenesin 514.50mg 88.83%  Dextromethorphan HBr 23.25 mg 4.03% Hypromellose 27.50 mg4.75% Carbomer 8.25 mg 1.42% Colourant 0.22 mg 0.04% Mg Stearate 5.50 mg0.95% Total Layer 579.22 mg 100.00%  Total Tablet 759.22 mg 100.0% 

EXAMPLE 10

Tablet 1: Naproxen Ingredient mg/tablet % Weight Naproxen Sodium 110 mg73.33%  Microcrystalline Cellulose 14.5 mg 9.67% Povidone 4.75 mg 3.17%Mg Stearate 0.75 mg  0.7% Lactose 10.00 mg 6.67% Croscarmellose Sodium10.00 mg 6.67% Total Tablet 150.0 mg 100.0% 

Tablet 2: Immediate/Modified Release Dextromethorphan and GuaifenesinImmediate Release Layer Ingredient mg/tablet % Weight Guaifenesin 76.00mg 47.50% Dextromethorphan HBr 6.00 mg 3.75% Microcrystalline Cellulose70.02 mg 43.76% Hypromellose 4.00 mg 2.50% Sodium Starch Glycolate 3.18mg 1.99% Mg Stearate 0.80 mg 0.50% Total Layer 160.00 mg 100.00%

Modified Release Layer Ingredient mg/tablet % Weight Guaifenesin 424.00mg 91.74%  Dextromethorphan HBr 24.00 mg 5.19% Carbomer 9.90 mg 2.14%Colourant 0.26 mg 0.06% Mg Stearate 4.00 mg 0.87% Total Layer 462.16 mg100.00%  Total Tablet 622.16 mg 100.0% 

EXAMPLE 11

Tablet 1: Naproxen Ingredient mg/tablet % Weight Naproxen Sodium 110 mg72.37%  Microcrystalline Cellulose 9.25 mg 6.09% Povidone 4.75 mg 3.13%Mg Stearate 1.00 mg 0.66% Sodium Lauryl Sulphate 25.00 mg 16.45% Croscarmellose Sodium 2.00 mg 1.32% Total Tablet 150.0 mg 100.0% 

Tablet 2: Immediate/Modified Release Dextromethorphan and GuaifenesinImmediate Release Layer Ingredient mg/tablet % Weight Guaifenesin 85.5mg 47.50% Dextromethorphan HBr 6.75 mg 3.75% Microcrystalline Cellulose78.77 mg 43.76% Hypromellose 4.50 mg 2.50% Sodium Starch Glycolate 3.58mg 1.99% Mg Stearate 0.90 mg 0.50% Total Layer 180.00 mg 100.00%

Modified Release Layer Ingredient mg/tablet % Weight Guaifenesin 514.50mg 88.83%  Dextromethorphan HBr 23.25 mg 4.03% Hypromellose 27.50 mg4.75% Carbomer 8.25 mg 1.42% Colourant 0.22 mg 0.04% Mg Stearate 5.50 mg0.95% Total Layer 579.22 mg 100.00%  Total Tablet 759.22 mg 100.0% 

EXAMPLE 12

Tablet 1: Naproxen Ingredient mg/tablet % Weight Naproxen Sodium 110 mg72.37%  Microcrystalline Cellulose 9.25 mg 6.09% Povidone 4.75 mg 3.13%Mg Stearate 1.00 mg 0.66% Sodium Lauryl Sulphate 25.00 mg 16.45% Croscarmellose Sodium 2.00 mg 1.32% Total Tablet 150.0 mg 100.0% 

Tablet 2: Immediate/Modified Release Dextromethorphan and GuaifenesinImmediate Release Layer Ingredient mg/tablet % Weight Guaifenesin 76.00mg 47.50% Dextromethorphan HBr 6.00 mg 3.75% Microcrystalline Cellulose70.02 mg 43.76% Hypromellose 4.00 mg 2.50% Sodium Starch Glycolate 3.18mg 1.99% Mg Stearate 0.80 mg 0.50% Total Layer 160.00 mg 100.00%

Modified Release Layer Ingredient mg/tablet % Weight Guaifenesin 424.00mg 91.74%  Dextromethorphan HBr 24.00 mg 5.19% Carbomer 9.90 mg 2.14%Colourant 0.26 mg 0.06% Mg Stearate 4.00 mg 0.87% Total Layer 462.16 mg100.00%  Total Tablet 622.16 mg 100.0% 

EXAMPLE 13 Composite Tablet

Immediate Release Layer Ingredient mg/tablet % Weight Guaifenesin 140 mg28.58%  Dextromethorphan HBr 8 mg 1.63% Naproxen Sodium 110 mg 22.45% Microcrystalline Cellulose 60 mg 12.24%  Povidone 11 mg 2.25%Croscarmellose sodium 26 mg 5.31% Crospovidone 9.8 mg 2.00% Sodiumlauryl sulfate 25 mg 5.10% Bicarbonate 100 mg 20.41%  Mg Stearate 0.1 mg0.02% Total Tablet 489.9 mg 100.0% 

Modified Release Layer Ingredient mg/tablet % Weight Guaifenesin 460 mg84.73%  Dextromethorphan HBr 22 mg 4.05% Hypromellose 28 mg 5.16%Hydroxy ethyl cellulose 14 mg 2.58% Microcrystalline Cellulose 17 mg3.13% Colourant 0.1 mg 0.02% Mg Stearate 1.8 mg 0.33% Total Layer 542.9mg 100.0% 

EXAMPLE 14 Composite Tablet

Immediate Release Layer Ingredient mg/tablet % Weight Guaifenesin 200 mg45.25% Dextromethorphan HBr 10 mg  2.26% Naproxen Sodium 110 mg 24.89%Microcrystalline Cellulose 45 mg 10.18% Povidone 11 mg  2.49%Crospovidone 65 mg 14.71% Mg Stearate 1 mg  0.23% Total Tablet 442 mg100.0%

Modified Release Layer Ingredient mg/tablet % Weight Guaifenesin 400 mg84.54%  Dextromethorphan HBr 20 mg 4.23% Hypromellose 24.5 mg 5.18%Hydroxy ethyl cellulose 12.25 mg 2.59% Microcrystalline Cellulose 14.75mg 3.12% Colourant 0.1 mg 0.02% Mg Stearate 1.55 mg 0.33% Total Layer473.15 mg 100.0% 

EXAMPLE 15 Composite Tablet

Immediate Release Layer Ingredient mg/tablet % Weight Guaifenesin 95 mg24.26%  Dextromethorphan HBr 7.5 mg 1.92% Naproxen Sodium 110 mg 28.09% Microcrystalline Cellulose 60 mg 15.32%  Povidone 11 mg 2.81%Croscarmellose sodium 15 mg 3.83% Crospovidone 8.00 mg 2.00% SodiumLauryl Sulfate 25 mg 5.10% Sodium Bicarbonate 60 mg 20.41%  Mg Stearate0.1 mg 0.03% Total Layer 391.6 mg 100.0% 

Modified Release Layer Ingredient mg/tablet % Weight Guaifenesin 505 mg89.35%  Dextromethorphan HBr 22.5 mg 3.98% Hypromellose 25 mg 4.42%Carbomer 7.5 mg 1.33% Colourant 0.2 mg 0.04% Mg Stearate 5.0 mg 0.88%Total Layer 565.2 mg 100.0% 

EXAMPLE 16 Composite Tablet

Immediate Release Layer Ingredient mg/tablet % Weight Guaifenesin 95 mg27.34% Dextromethorphan HBr 7.5 mg  2.16% Naproxen Sodium 110 mg 31.65%Microcrystalline Cellulose 75 mg 21.58% Povidone 11 mg  3.17%Croscarmellose sodium 40 mg 11.51% Crospovidone 8.00 mg  2.30% MgStearate 1 mg  0.29% Total 347.5 mg 100.0%

Modified Release Layer

Modified Release Layer Ingredient mg/tablet % Weight Guaifenesin 505 mg89.35%  Dextromethorphan HBr 22.5 mg 3.98% Hypromellose 25 mg 4.42%Carbomer 7.5 mg 1.33% Colourant 0.2 mg 0.04% Mg Stearate 5.0 mg 0.88%Total Layer 565.2 mg 100.0% 

EXAMPLE 17 Composite Tablet

Immediate Release Layer Ingredient mg/tablet % Weight Guaifenesin 95 mg24.32%  Dextromethorphan HBr 7.5 mg 1.92% Naproxen Sodium 110 mg 28.16% Microcrystalline Cellulose 60 mg 15.36%  Povidone 11 mg 2.82%Croscarmellose sodium 22 mg 5.63% Sodium Lauryl Sulphate 25.00 mg 6.40%Sodium Bicarbonate 60.00 mg 15.36%  Mg Stearate 0.1 mg 0.03% Total 390.6mg 100.0% 

Modified Release Layer Ingredient mg/tablet % Weight Guaifenesin 505 mg89.35%  Dextromethorphan HBr 22.5 mg 3.98% Hypromellose 25 mg 4.42%Carbomer 7.5 mg 1.33% Colourant 0.2 mg 0.04% Mg Stearate 5.0 mg 0.88%Total Layer 565.2 mg 100.0% 

EXAMPLE 18 Composite Tablet

Immediate Release Layer Ingredient mg/tablet % Weight Guaifenesin 95 mg27.98% Dextromethorphan HBr 7.5 mg  2.21% Naproxen Sodium 110 mg 32.40%Microcrystalline Cellulose 75 mg 22.09% Povidone 11 mg  3.24%Croscarmellose sodium 40 mg 11.78% Mg Stearate 1 mg  0.29% Total 339.5mg 100.0%

Modified Release Layer Ingredient mg/tablet % Weight Guaifenesin 505 mg 89.35%  Dextromethorphan HBr 22.5 mg  3.98% Hypromellose  25 mg 4.42%Carbomer 7.5 mg 1.33% Colourant 0.2 mg 0.04% Mg Stearate 5.0 mg 0.88%Total Layer 565.2 mg  100.0% 

The tablets of the example embodiments of the present invention can bemade using standard tableting procedures well-known to the personskilled in the art.

The bi-layer tablet may be manufactured according to any method known tothose of skill in the art. The resulting tablet may comprise the twoportions compressed against one another so that the face of each portionis exposed as either the top or bottom of the tablet, or the resultingtablet may comprise the sustained release portion in the centre coatedby the immediate release portion so that only the immediate releaseportion is exposed. In a preferred embodiment, a bi-layer tablet of thepresent invention comprises the two portions compressed against oneanother so that the face of each portion is exposed.

The final dosage form can be made by inserting both theimmediate-release naproxen tablet and the immediate-release/sustained ormodified release guaifenesin/dextromethorphan tablet into a gelatincapsule which is then sealed.

Furthermore, the composite tablets of Examples 3 and 4 are final dosageforms and need not, though they can, be inserted into a suitablecapsule.

An advantage of the present invention is that there is provided acomposition that provides multi-symptom cough/cold/flu relief for 12hours. Currently, there are no other products that offer all of thesesignificant benefits to consumers.

A further advantage is that there is provided a composition whichcomprises naproxen, guaifenesin and dextromethorphan in a single doseyet avoids any impact on the dissolution rate of either guaifenesin ordextromethorphan by naproxen.

The composition of the present invention also provides for moreconsistent release of both guaifenesin and dextromethorphan whencompared to known products in various pH conditions and when exposed tovarious agitation speeds. For example purposes only, these novelformulations have been shown to improve the consistency ofdextromethorphan release after 6 hours by 29% and guaifenesin releaseafter 6 hours by 52% and 71%.

Further modifications and improvements can be made without departingfrom the scope of the invention described herein.

1. A pharmaceutical composition comprising a pharmaceutically effectiveamount of guaifenesin, naproxen and at least one further active which isselected to be an antitussive, a decongestant or an antihistamine.
 2. Acomposition as claimed in claim 1, wherein the at least one other drugis selected from an antitussive such as dextromethorphan, codeine,codeine phosphate, codeine sulphate, diphenhydramine citrate, anddiphenhydramine hydrochloride, a decongestant such as phenylephrinehydrochloride, phenylpropanolamine hydrochloride, pseudoephedrine orephedrine, an antihistamine such as chlorpheniramine maleate,brompheniramine maleate, phenindamine tartrate, pyrilamine maleate,doxylamine succinate, phenyltoloxamine citrate, diphenhydraminehydrochloride, promethazine, and clemastine fumerate, or a combinationthereof.
 3. A composition as claimed in claim 2, wherein the at leastone other drug is dextromethorphan or pseudoephedrine.
 4. A compositionas claimed in claim 3, wherein the expectorant is guaifenesin, theanalgesic is naproxen and the antitussive is dextromethorphan.
 5. Acomposition as claimed in claim 4, wherein the ratio ofguaifenesin:naproxen:dextromethorphan is from about 40:8:1 to about10:3:1.
 6. A composition as claimed in claim 5, wherein the ratio ofguaifenesin:naproxen:dextromethorphan is from 22:4:1 to 17:3:1.
 7. Acomposition as claimed in claim 5, wherein the ratio ofguaifenesin:naproxen:dextromethorphan is 20:3.67:1.
 8. A composition asclaimed in claim 1, wherein the ratio of guaifensin:naproxen is fromabout 1:1 to about 10:1.
 9. A composition as claimed in claim 8, whereinthe ratio of guaifensin:naproxen is from about 2:1 to about 7:1.
 10. Acomposition as claimed in claim 8, wherein the ratio ofguaifensin:naproxen is from about 4:1 to about 6:1.
 11. A composition asclaimed in claim 2, wherein the ratio of naproxen:dextromethorphan isfrom about 1:1 to about 10:1.
 12. A composition as claimed in claim 11,wherein the ratio of naproxen:dextromethorphan is from about 2:1 toabout 7:1.
 13. A composition as claimed in claim 11, wherein the ratioof wherein the ratio of naproxen:dextromethorphan is from about 3:1 toabout 5:1.
 14. A composition as claimed in claim 1, wherein compositioncomprises immediate and sustained release portions.
 15. A composition asclaimed in claim 14, wherein the composition is provided with bothsustained-release and immediate-release portions comprising theexpectorant.
 16. A composition as claimed in claim 14, wherein thenaproxen is incorporated into the composition such that it is the soleactive in the portion in which it is contained.
 17. A composition asclaimed in claim 14, wherein the composition is provided with bothsustained-release and immediate-release portions comprising guaifenesin.18. A composition as claimed in claim 14, wherein the compositioncomprises a first immediate release portion which comprises guaifenesinand a decongestant or an antitussive, a second immediate release portionwhich comprises naproxen, and a sustained release portion whichcomprises guaifenesin.
 19. A composition as claimed in claim 1, whereinthe composition comprises: (a) 50-85% Guaifenesin; (b) up to 5%Dextromethorphan or a pharmaceutically acceptable salt thereof; and (c)5-30% Naproxen or a pharmaceutically acceptable salt thereof.
 20. Acomposition as claimed in claim 1, wherein the composition comprises:(a) 55-65% Guaifenesin; (b) 1-5% Dextromethorphan or a pharmaceuticallyacceptable salt thereof; (c) 5-15% Naproxen or a pharmaceuticallyacceptable salt thereof; (d) 1-10% Controlled release polymers; (e)0.1-10% Binders; (f) 0.1-5% Disintegrants; (g) 5-25% Diluents; and (h)up to 1% Lubricants.
 21. A composition as claimed in claim 20, whereinthe composition comprises: (a) 55-65% Guaifenesin; (b) 1-5%Dextromethorphan or a pharmaceutically acceptable salt thereof; (c)5-15% Naproxen or a pharmaceutically acceptable salt thereof; (d) 1-8%Hypromellose; (e) 10-25% Microcrystalline cellulose; (f) 0.1-2.5%Povidone; (g) 0.1-4.0% Croscarmellose Sodium; (h) 0.1-2.0% HydroxyethylCellulose; and (i) up to 1% Magnesium stearate.
 22. A composition asclaimed in claim 21, wherein the composition comprises: (a) 58-63%Guaifenesin; (b) 2-3.5% Dextromethorphan or a pharmaceuticallyacceptable salt thereof; (c) 10-12% Naproxen or a pharmaceuticallyacceptable salt thereof; (d) 1-2% Hypromellose; (e) 15-25%Microcrystalline cellulose; (f) 1-2% Povidone; (g) 0.5-2.5%Croscarmellose sodium; (h) 0.5-1% Hydroxyethyl cellulose; and (i) up to0.5% Magnesium stearate.
 23. A composition as claimed in claim 20,wherein the composition comprises: (a) 55-65% Guaifenesin; (b) 1-5%Dextromethorphan or a pharmaceutically acceptable salt thereof; (c)5-15% Naproxen or a pharmaceutically acceptable salt thereof; (d) 1-8%Hypromellose; (e) 10-25% Microcrystalline cellulose; (f) 0.1-2.5%Povidone; (g) 0.1-2.0% Carbomer; (h) 0.1-2.0% Sodium Starch Glycolate;(i) up to 1% Magnesium stearate; and
 24. A composition as claimed inclaim 23, wherein the composition comprises: (a) 59-65% Guaifenesin; (b)3-5% Dextromethorphan or a pharmaceutically acceptable salt thereof; (c)10-12% Naproxen or a pharmaceutically acceptable salt thereof; (d) 1-6%Hypromellose; (e) 10-20% Microcrystalline cellulose; (f) 0.3-1%Povidone; (g) 0.5-1% Carbomer; (h) 0.1-0.5% Sodium Starch Glycolate; and(i) up to 1% Magnesium stearate.
 25. A composition as claimed in claim20, wherein the composition comprises: (a) 59-65% Guaifenesin; (b) 3-5%Dextromethorphan or a pharmaceutically acceptable salt thereof; (c)10-12% Naproxen or a pharmaceutically acceptable salt thereof; (d) 1-6%Hypromellose; (e) 10-20% Microcrystalline cellulose; (f) 0.3-1%Povidone; (g) 0.5-1% Carbomer; (h) 1-2% Croscarmellose sodium; (i)0.1-0.5% Sodium Starch Glycolate; and (j) up to 1% Magnesium stearate.26. A composition as claimed in claim 1, wherein the compositioncomprises: (a) 64-69% Guaifenesin; (b) 3-5% Dextromethorphan or apharmaceutically acceptable salt thereof; (c) 12-15% Naproxen or apharmaceutically acceptable salt thereof; (d) 3-5% Hypromellose; (e)9-15% Microcrystalline cellulose; (f) 0.4-0.65% Povidone; (g) 0.75-1.3%Carbomer; (h) 0.5-1% Magnesium stearate; and (i) 0.25-0.5% Sodium starchglycolate.
 27. A composition as claimed in claim 26, wherein thecomposition further comprises: (j) 0.5-1.5% Lactose; (k) 2.5-3.5% Sodiumlauryl sulphate; and (l) 0.1-1.5% Croscarmellose sodium.
 28. Acomposition as claimed in claim 1, wherein the composition comprises:(a) 64-69% Guaifenesin; (b) 3-5% Dextromethorphan or a pharmaceuticallyacceptable salt thereof; (c) 12-15% Naproxen or a pharmaceuticallyacceptable salt thereof; (d) 0.1-0.6% Hypromellose; (e) 9-15%Microcrystalline cellulose; (f) 0.4-0.65% Povidone; (g) 0.75-1.3%Carbomer; (h) 0.5-1% Magnesium stearate; and (i) 0.25-0.5% Sodium starchglycolate.
 29. A composition as claimed in claim 28, wherein thecomposition further comprises one or more of: (j) 0.5-1.5% Lactose; (k)2.5-3.5% Sodium lauryl sulphate; and (l) 0.1-1.5% Croscarmellose sodium.30. A composition as claimed in claim 1, wherein the compositioncomprises: (a) 63-66% Guaifenesin; (b) 3-5% Dextromethorphan or apharmaceutically acceptable salt thereof; (c) 10-12% Naproxen or apharmaceutically acceptable salt thereof; (d) 1.75-3.0% Hypromellose;(e) 11-13% Microcrystalline cellulose; (f) 1-2% Povidone; (g) 0.5-0.75%Croscarmellose Sodium; (h) 1-2% Carbomer; (i) 0.1-0.5% Magnesiumstearate; and (j) 0.5-1.5% Lactose.
 31. A composition as claimed inclaim 30, wherein the composition further includes: (k) 2-3% SodiumLauryl Sulphate.
 32. A composition as claimed in claim 1, wherein thecomposition comprises: (a) 64-66% Guaifenesin; (b) 3-5% Dextromethorphanor a pharmaceutically acceptable salt thereof; (c) 11-13% Naproxen or apharmaceutically acceptable salt thereof; (d) 1.75-3.0% Hypromellose;(e) 6-8.5% Microcrystalline cellulose; (f) 1-2% Povidone; (g) 1-5%Croscarmellose Sodium; (h) 0.5-1% Carbomer; (i) 0.5-1% Magnesiumstearate; and (j) 0.5-1% Crospovidone.
 33. A composition as claimed inclaim 32, wherein the composition further includes one or more of: (k)2-3% Sodium Lauryl Sulphate; and (l) 6-7% Sodium Bicarbonate.
 34. Acomposition as claimed in claim 1, wherein the composition comprises:(a) 64-66% Guaifenesin; (b) 3-5% Dextromethorphan or a pharmaceuticallyacceptable salt thereof; (c) 11-13% Naproxen or a pharmaceuticallyacceptable salt thereof; (d) 1.75-3.0% Hypromellose; (e) 6-8.5%Microcrystalline cellulose; (f) 1-2% Povidone; (g) 1-5% CroscarmelloseSodium; (h) 0.5-1% Carbomer; and (i) 0.5-1% Magnesium stearate.
 35. Acomposition as claimed in claim 1, wherein the composition comprises:(a) 62-65% Guaifenesin; (b) 3-5% Dextromethorphan or a pharmaceuticallyacceptable salt thereof; (c) 11-13% Naproxen or a pharmaceuticallyacceptable salt thereof; (d) 1.75-3.0% Hypromellose; (e) 6-8.5%Microcrystalline cellulose; (f) 1-2% Povidone; (g) 1-5% CroscarmelloseSodium; (h) 0.5-1% Carbomer; and (i) 0.5-1% Magnesium stearate; (j) 2-3%Sodium Lauryl Sulphate; and (k) 5-8% Sodium Bicarbonate.
 36. Acomposition as claimed in claim 1, wherein the composition comprises:(a) 58-60% Guaifenesin; (b) 2-3% Dextromethorphan or a pharmaceuticallyacceptable salt thereof; (c) 10-11% Naproxen or a pharmaceuticallyacceptable salt thereof; (d) 2-3% Hypromellose; (e) 7-8%Microcrystalline cellulose; (f) 1-2% Povidone; (g) 2-3% CroscarmelloseSodium; (h) 0.1-0.2% Magnesium stearate; (i) 0.5-1% Crospovidone; (j)1-3% Hydroxyethyl cellulose; (k) 2-3% Sodium Lauryl Sulphate; and (l)9-10% Sodium bicarbonate.
 37. A composition as claimed in claim 1,wherein the composition comprises: (a) 64-66% Guaifenesin; (b) 3-5%Dextromethorphan or a pharmaceutically acceptable salt thereof; (c)11-13% Naproxen or a pharmaceutically acceptable salt thereof; (d) 2-3%Hypromellose; (e) 6-7% Microcrystalline cellulose; (f) 1-2% Povidone;(g) 0.1-0.5% Magnesium stearate; (h) 7-10% Crospovidone; and (i) 1-3%Hydroxyethyl cellulose.
 38. A pharmaceutical dosage form which comprisesat least three distinct portions wherein two of the portions haveimmediate release characteristics and a third portion has modifiedrelease characteristics, wherein one of the immediate release portionscomprises an expectorant and a second active which is an antitussive ora decongestant and the second immediate release portion comprises ananalgesic having a half-life of twelve hours and wherein the modifiedrelease portion comprises guaifenesin and a second active which is anantitussive or a decongestant.
 39. A pharmaceutical dosage form asclaimed in claim 38, wherein the dosage form comprises a firstcomposition which comprises both immediate and modified release portionsof the expectorant and the second active which is an antitussive or adecongestant and a second composition which comprises an analgesichaving a therapeutic effect of twelve hours.
 40. A pharmaceutical dosageform as claimed in claim 38, wherein the analgesic is the sole active inthe portion in which it is contained.
 41. A composition as claimed inclaim 1, wherein an analgesic-containing immediate release portioncomprises: (a) 50-52% Naproxen or a pharmaceutically acceptable saltthereof; (b) 35-40% Microcrystalline cellulose; (c) up to 5% Povidone;(d) 5-8% Croscarmellose sodium; and (e) up to 1% Magnesium stearate. 42.A composition as claimed in claim 1 wherein an analgesic-containingimmediate release portion comprises: (a) 70-75% Naproxen or apharmaceutically acceptable salt thereof; (b) 20-25% Microcrystallinecellulose; (c) up to 5% Povidone; and (d) up to 1% Magnesium stearate.43. A composition as claimed in claim 1, wherein an analgesic-containingimmediate release portion comprises: (a) 70-75% Naproxen or apharmaceutically acceptable salt thereof; (b) 5-10% Microcrystallinecellulose; (c) up to 5% Povidone; (d) up to 1% Magnesium stearate; (e)5-10% Lactose; and (f) up to 5% Croscarmellose sodium.
 44. A compositionas claimed in claim 1, wherein an analgesic-containing immediate releaseportion comprises: (a) 70-75% Naproxen or a pharmaceutically acceptablesalt thereof; (b) 5-10% Microcrystalline cellulose; (c) up to 5%Povidone; (d) up to 1% Magnesium stearate; (e) 5-10% Lactose; and (f)5-10% Croscarmellose sodium.
 45. A composition as claimed in claim 1,wherein an analgesic-containing immediate release portion comprises: (a)70-75% Naproxen or a pharmaceutically acceptable salt thereof; (b) 5-10%Microcrystalline cellulose; (c) up to 5% Povidone; (d) up to 1%Magnesium stearate; (e) up to 5% Lactose; and (f) 15-20% Sodium LaurylSulphate.
 46. A composition as claimed in claim 1, wherein ananalgesic-containing immediate release portion comprises: (a) 70-75%Naproxen or a pharmaceutically acceptable salt thereof; (b) 5-10%Microcrystalline cellulose; (c) up to 5% Povidone; (d) up to 1%Magnesium stearate; (e) up to 2% Croscarmellose sodium; and (f) 15-20%Sodium Lauryl Sulphate.
 47. A composition as claimed in claim 1, whereina guaifenesin-containing immediate release portion comprises: (a) 30-40%Guaifenesin; (b) up to 5% Dextromethorphan or a pharmaceuticallyacceptable salt thereof; (c) 50-60% Microcrystalline cellulose; (d) upto 7% Povidone; (e) up to 7% Croscarmellose sodium; and (f) up to 1%Magnesium stearate.
 48. A composition as claimed in claim 1, wherein aguaifenesin-containing immediate release portion comprises: (a) 40-50%Guaifenesin; (b) up to 5% Dextromethorphan or a pharmaceuticallyacceptable salt thereof; (c) 40-50% Microcrystalline cellulose; (d) upto 5% Hypromellose; (e) up to 5% Sodium starch glycolate; and (f) up to1% Magnesium stearate.
 49. A composition as claimed in claim 1, whereina guaifenesin-containing immediate release portion comprises: (a) 50-65%Guaifenesin; (b) up to 5% Dextromethorphan or a pharmaceuticallyacceptable salt thereof; (c) 25-40% Microcrystalline cellulose; (d) upto 5% Povidone; (e) up to 5% Croscarmellose sodium; and (f) up to 1%Magnesium stearate.
 50. A composition as claimed in claim 1, wherein amodified release portion comprises: (a) 80-90% Guaifenesin; (b) up to 5%Dextromethorphan or a pharmaceutically acceptable salt thereof; (c) upto 10% Hypromellose; (d) up to 5% Carbomer; and (e) up to 1.55%Magnesium stearate.
 51. A composition as claimed in claim 1, wherein amodified release portion comprises: (a) 80-90% Guaifenesin; (b) 3-6%Dextromethorphan or a pharmaceutically acceptable salt thereof; (c) upto 5% Hypromellose; (d) up to 2% Hydroxy ethylcellulose; (e) up to 5%Microcrystalline cellulose; and (f) up to 1% Magnesium stearate.
 52. Acomposition as claimed in claim 1, wherein a modified release portioncomprises: (a) 80-90% Guaifenesin; (b) 3-6% Dextromethorphan or apharmaceutically acceptable salt thereof; (c) up to 5% Hypromellose; (d)up to 5% Hydroxy ethylcellulose; (e) up to 5% Microcrystallinecellulose; and (f) up to 1% Magnesium stearate.
 53. A composition asclaimed in claim 1, wherein a modified release portion comprises: (a)85-90% Guaifenesin; (b) 4-5% Dextromethorphan or a pharmaceuticallyacceptable salt thereof; (c) 3-6% Hypromellose; (d) 1-3% Carbomer; and(e) 0.5-1% Magnesium stearate.
 54. A composition as claimed in claim 1,wherein a modified release portion comprises: (a) 90-93% Guaifenesin;(b) 4-6% Dextromethorphan or a pharmaceutically acceptable salt thereof;(c) 1-3% Carbomer; and (d) 0.5-1% Magnesium stearate.